DESC:FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See section 10; Rule 13]

TITLE: “SOLID PHARMACEUTICAL SUBLINGUAL ORAL DOSAGE COMPOSITION AND METHOD TO PRODUCE THEREOF”

Name and Address of the Applicant:
Health Diary Pvt Ltd.
SY -252 FP-84/B PLOT-A TPS-5,
B/S CHANDRA PRBHADIGAMBER TEMPLE, PARLE POINT, SURAT- 395007

Nationality: Indian

The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE OF THE INVENTION

SOLID PHARMACEUTICAL SUBLINGUAL ORAL DOSAGE COMPOSITION AND METHOD TO PRODUCE THEREOF

BACKGROUND

Technical Field
[0001] The inventive subject matter presented herein is generally directed toward a fast-acting painkiller delivery through the sublingual route. More particularly, embodiments are related to a solid pharmaceutical sublingual oral dosage composition containing a diclofenac-free acid.

Description of the Related Art
[0002] The subject matter discussed in the background section should not be assumed to be prior art merely as a result of its mention in the background section. Similarly, a problem mentioned in the background section or associated with the subject matter of the background section should not be assumed to have been previously recognized in the prior art. The subject matter in the background section merely represents different approaches, which in and of themselves may also be inventions.
[0003] Painkillers when taken orally cause gastric irritation and take three to six hours for them to produce the action. US patent US9415029B2 issued to Jagat Singh talks about a method for applying topical agents to a knee of a patient with pain. The method comprising: applying a first medication comprising a topical diclofenac preparation to an area of the knee of said patient to treat osteoarthritis of the knee of said patient, wherein the topical diclofenac preparation consists of 2% w/w diclofenac sodium; about 40% to about 50% w/w dimethyl sulfoxide; about 23-29% w/w ethanol; about 10-12% w/w propylene glycol; about 2.5% w/w hydroxypropyl cellulose; and water to make 100% w/w; and wherein the topical diclofenac preparation has a viscosity of 500-5000 centipoise; waiting for the treated area to dry; and subsequently applying a second prescription medication consisting of a topical medication other than said first medication to said treated area after said the treated area is dry, wherein said subsequent application occurs during a course of treatment of the patient with said topical diclofenac preparation.
[0004] PCT application WO2014009793A1 filed by Zoppetti Giorgio discloses a pharmaceutical composition with anti-inflammatory and analgesic activity to be delivered by a vaporization (spray) system for external use comprising, as the active ingredient, diclofenac, 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid, preferably as an organic base salt thereof, in particular as secondary or tertiary amine salt and more particularly as a cyclic, tertiary amine salt. Said active ingredient is dissolved in a volatile silicon in the presence of a 2-4C alcohol mixture and is free from water and non-volatile silicon.
[0005] However, the above-mentioned existing painkiller compositions when kept under the tongue will dissolve in approximately 10-15 minutes and action will start from about 10 minutes which may last for nearly 6-7 hrs and do not produce any gastric irritations. This specification recognizes that there is a long-felt need in the healthcare industry to mask the intensely bitter taste of diclofenac and to formulate a fast-acting, taste-masked sublingual tablet formulation. Further, there is a need for a sublingual pharmaceutical composition containing diclofenac, derivative, or polymorph thereof, which overcomes the deficiencies of the prior art with increased patient compliance and absorption rate of the drug via the blood vessels under the tongue.
[0006] Further limitations and disadvantages of conventional approaches will become apparent to one of ordinary skill in the art through the comparison of described systems with some aspects of the present disclosure, as set forth in the remainder of the present application and with reference to the drawings.

SUMMARY

[0007] A fast-acting painkiller delivery through the sublingual route is provided and shown in and/or described in connection with the figures.
[0008] According to embodiments illustrated herein, there is provided a method for obtaining a solid pharmaceutical sublingual oral dosage composition containing a diclofenac-free acid. The method includes a step of dispensing a plurality of first input materials comprising diclofenac free acid, Mannitol, and artificial cherry flavor. Then, the dispensed diclofenac-free acid, mannitol and artificial cherry flavor are sieved through an appropriate size screen mesh. The method includes a step of sieving a plurality of second input materials comprising sodium starch glycolate and Croscarmellose sodium through the appropriate size screen mesh. The method includes a step of blending the first input materials and the second input materials to obtain a first uniform blend. The method includes a step of dispensing a plurality of third input materials comprising microcrystalline cellulose, aspartame, and colloidal silicon dioxide. Then, the microcrystalline cellulose, aspartame, and colloidal silicon dioxide are sieved through the appropriate size screen mesh. The method includes a step of blending the third input materials with the first uniform blend to obtain a second uniform blend. The method includes a step of dispensing a fourth input material comprising sodium stearyl fumarate. Then the sodium stearyl fumarate is sieved through the appropriate size screen mesh. The method includes a step of blending the fourth input material with the second uniform blend to obtain a final uniform blend. The final uniform blend comprises the solid pharmaceutical sublingual oral dosage composition containing the diclofenac-free acid.
[0009] The method includes a step of compressing the solid pharmaceutical sublingual oral dosage composition to obtain a plurality of tablets. The method includes a step of performing an in-process sampling such as content uniformity/weight variation hardness/thickness. The method includes a step of packaging the tablets which are delivered through the sublingual route.
[0010] In an aspect, the solid pharmaceutical sublingual oral dosage composition is compressed by a Rotary Tablet Press.
[0011] In an aspect, the sieve is 425 pm (particle size mesh) sieve.
[0012] In an aspect, the solid pharmaceutical sublingual oral dosage composition has an average weight (mg) of about 235 mg to 245 mg.
[0013] In an aspect, the solid pharmaceutical sublingual oral dosage composition comprising 46.560 mg of diclofenac free acid, 123.440 mg of mannitol, 15.000 mg of artificial cherry flavor, 15.000 mg of sodium starch glycolate, 10.000 mg of croscarmellose sodium, 15.000 mg of microcrystalline cellulose, 3.000 mg of aspartame, 4.000 mg of colloidal silicon dioxide, and 8.000 mg of sodium stearyl fumarate.
[0014] Accordingly, one advantage of the present inventive subject matter is that it provides a solid pharmaceutical dosage composition for sublingual administration containing diclofenac or a pharmaceutically acceptable salt, derivative or polymorph thereof, as an active ingredient, which disintegrates fast without leaving an unpleasant taste in the mouth, and which show good physicochemical stability and low friability, rendering them suitable for normal packaging and storing procedures.
[0015] An aspect of the present disclosure relates to a solid pharmaceutical dosage formulation for sublingual administration containing diclofenac, derivative or polymorph thereof, as an active ingredient, having increased chemical stability of the active ingredient, sufficient self-life, and good pharmaco-technical properties.
[0016] Accordingly, one advantage of the present inventive subject matter is that it provides a quick-release formulation, capable of delivering the drug directly to the blood circulation, and also capable of achieving rapidly the maximum drug levels in the plasma.
[0017] These features and advantages of the present disclosure may be appreciated by reviewing the following description of the present disclosure, along with the accompanying figures wherein like reference numerals refer to like parts.

BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The accompanying drawings illustrate the embodiments of methods, compositions, and other aspects of the disclosure. A person with ordinary skills in the art will appreciate that the illustrated element boundaries (e.g., boxes, groups of boxes, or other shapes) in the figures represent an example of the boundaries of such elements. In some examples, one element may be designed as multiple elements, or multiple elements may be designed as one element. In some examples, an element shown as an internal component of one element may be implemented as an external component in another and vice versa. Furthermore, the elements may not be drawn to scale.
[0019] Various embodiments will hereinafter be described in accordance with the appended drawings, which are provided to illustrate, not limit, the scope, wherein similar designations denote similar elements, and in which:
[0020] FIG. 1 illustrates a flowchart of a method for obtaining a solid pharmaceutical sublingual oral dosage composition containing a diclofenac-free acid or a pharmaceutically acceptable salt, in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION
[0021] The present disclosure is best understood with reference to the detailed figures and description set forth herein. Various embodiments of the present systems and methods have been discussed with reference to the figures. However, those skilled in the art will readily appreciate that the detailed description provided herein including the figures are presented for explanatory purposes and the embodiments extend beyond the currently described embodiments. For instance, the teachings and results presented in any particular described application may yield multiple alternative approaches and may be implemented in any suitable manner.
[0022] The described embodiments may be implemented manually, automatically, and/or a combination of thereof. The term “method” refers to manners, means, techniques, and procedures for accomplishing any task including, but not limited to, those manners, means, techniques, and procedures either known to the person skilled in the art or readily developed from existing manners, means, techniques and procedures by practitioners of the art to which the embodiments pertains. Persons skilled in the art will envision many other possible variations that are within the scope of the claimed subject matter.
[0023] According to an embodiment herein, the present disclosure provides a solid pharmaceutical sublingual oral dosage composition containing a diclofenac-free acid or a pharmaceutically acceptable salt. The diclofenac-free acid acts as an active pharmaceutical ingredient (API) to provide the best pain relief. The active ingredient contained in a dosage form is “bioavailability, if when administered in a dosage form is released from the dosage form, absorbed, and reaches concentration levels in plasma. The solid pharmaceutical composition is suitable for a tablet formulation prepared by dry/wet granulation, by the adequate release rate of the active ingredient, and storage stability achieved by employing excipients indicated for the treatment of acute, subacute, and chronic musculoskeletal disorders. The solid pharmaceutical composition employs an effective amount of pH-dependent excipients as a taste masking agent to reduce the burning of the mucosa occurring when diclofenac-free acid salt which contacts the mucosa, such as below the tongue and buccal mucosa. The excipients provide an appropriate dissolution rate and stability of the finished dosage form.
[0024] In an embodiment, additional excipients are incorporated in the formulation to improve the physicochemical properties of the composition and to dissolve fast under the tongue.
[0025] In an embodiment, the pharmaceutical composition contains one or more additional formulation excipients such as diluents, disintegrates, binders, lubricants, glidants, and flavoring agents to increase the stability of the drug and the self-life of the pharmaceutical product to act fast on pain gateway for better relief to the patient.
[0026] The above-mentioned chemicals, Mannitol (Pearlitol SD 200); croscarmellose sodium USNF; Microcrystalline Cellulose (Avicel PH-112); Aspartame USNF (Aminosweet Powder); and Colloidal silicon dioxide USNF (Aerosil ® 200 Primojel® Sodium starch glycolate Type A help to deliver the drug fast under the tongue. Once dissolved under the tongue they go directly to the heart and enter the blood system, and then go to the pain center in the midbrain and block the gateway of pain. This is all done in 10 minutes, as the maximum drug is released.
[0027] FIG. 1 illustrates a flowchart 100 of a method for obtaining a solid pharmaceutical sublingual oral dosage composition containing a diclofenac-free acid or a pharmaceutically acceptable salt, in accordance with an embodiment of the present invention. The method includes a step 102 of dispensing a plurality of first input materials comprising diclofenac-free acid, mannitol, and artificial cherry flavor. The dispensed diclofenac-free acid, mannitol and artificial cherry flavor are sieved through an appropriate size screen mesh. The method includes a step 104 of sieving a plurality of second input materials comprising sodium starch glycolate and croscarmellose sodium through the appropriate size screen mesh. The method includes a step 106 of blending the first input materials and the second input materials to obtain a first uniform blend. The method includes a step 108 of dispensing a plurality of third input materials comprising microcrystalline cellulose, aspartame, and colloidal silicon dioxide. The microcrystalline cellulose, aspartame, and colloidal silicon dioxide are sieved through the appropriate size screen mesh. The method includes a step 110 of blending the third input materials with the first uniform blend to obtain a second uniform blend. The method includes a step 112 of dispensing a fourth input material comprising sodium stearyl fumarate. The sodium stearyl fumarate is sieved through the appropriate size screen mesh. The method includes a step 114 of blending the fourth input material with the second uniform blend to obtain a final uniform blend. The final uniform blend comprises the solid pharmaceutical sublingual oral dosage composition containing the diclofenac-free acid. In an embodiment, the appropriate size screen mesh has a sieve dimension of 425 pm.
[0028] The method includes a step 116 of compressing the solid pharmaceutical sublingual oral dosage composition to obtain a plurality of tablets. In an embodiment, the solid pharmaceutical sublingual oral dosage composition is compressed by a Rotary Tablet Press.
[0029] At step 118, an in-process sampling such as content uniformity/weight variation hardness/thickness is performed. Lastly, at step 120, bulk packaging of sublingual diclofenac tablet is performed which is completely (100%) delivered through the sublingual route.
[0030] In an embodiment, the solid pharmaceutical sublingual oral dosage composition has an average weight (mg) of about 235 mg to 245 mg. In an embodiment, the solid pharmaceutical sublingual oral dosage composition comprising 46.560 mg of diclofenac free acid, 123.440 mg of mannitol, 15.000 mg of artificial cherry flavor, 15.000 mg of sodium starch glycolate, 10.000 mg of croscarmellose sodium, 15.000 mg of microcrystalline cellulose, 3.000 mg of aspartame, 4.000 mg of colloidal silicon dioxide, and 8.000 mg of sodium stearyl fumarate.
[0031] The pharmaceutical composition of the present invention acts on the pain gate theory pathway and will be fast-acting. Further, the blood from the sublingual enters the heart and comes into circulation, and reaches the gate in a relatively fast time, hence the action will start fast. Hence, the formula of the present pharmaceutical composition will be a fast-acting pain killer with the least side effects.
[0032] A pharmaceutical composition comprising an active ingredient having an unpleasant taste (Diclofenac-class NSAIDs drug such as Diclofenac or salts thereof) is considered to be an active ingredient having taste characteristics which, when administered orally without any excipients, render the active ingredient and make it unpalatable to a subject. Further, the term "orally disintegrating”, used in the present invention, means that the pharmaceutical composition disintegrates in less than 90 seconds as measured by the in vitro disintegration test according to Ph.Eur. The empirical formula of Diclofenac is C14H11Cl2NO2. Further, the molecular weight of Diclofenac is 296.1 and the IUPAC name is 2-[2-(2,6-dichloroanilino)phenyl]acetic acid.
[0033] The composition according to the present invention preferably disintegrates in less than 40 seconds. The active ingredient contained in a dosage form is “bioavailable”, if when administered in a dosage form is released from the dosage form, absorbed, and reaches, at least the same, concentration levels in plasma as any of the marketed products containing the same quantity of the same active ingredient and intended for the same use. Sublingual tablets are designed to dissolve in a small quantity of saliva. After the tablet is placed in the mouth below the tongue, the patient should avoid eating, drinking, and possibly talking to keep the tablet in place and avoid swallowing saliva, since the saliva may contain dissolved drugs.
[0034] The main object of the present invention is to provide a quick-release composition. One of the main advantages of sublingual administration is the fact that it circumvents exposure of drugs to digestive enzymes in the gastrointestinal tract and avoids the first-pass effect from hepatic enzymes, immediately upon absorption. The direct access to blood circulation, in addition to the avoidance of any metabolism of the drug results in achieving quickly the maximum levels of the active ingredient in the plasma. Thus, a faster onset of pharmacological effects of the drug in patients is achieved in comparison to conventional oral delivery where the composition is swallowed. The mucosa of the mouth is well vascularized and well suited for the absorption of lipophilic, nonionized compounds. The sublingual route is particularly beneficial for drugs that require rapid onset of action. The sublingual tablets enable the administration of the drug by avoiding being swallowed. It also increases the absorption rate of the drug via the blood vessels under the tongue. In addition, diclofenac has an unpleasant and bitter taste, causes mild burning and contraction and the oral administration of said drug puts a burden on a patient and lowers compliance. Further, compounds with unpleasant taste such as diclofenac stimulate saliva flow which leads to increased swallowing of the drug. Thus, the unpleasant taste of diclofenac needs to be masked to reduce the burning occurring when the active ingredient contacts the mucous membrane epithelium of the mouth. The solid pharmaceutical composition for the sublingual administration of the present invention is characterized by physicochemical properties suitable for a tablet formulation prepared by dry/wet granulation, by the adequate release rate of the active ingredient, and storage stability achieved by employing excipients practically devoiding the tendency to interact with the active ingredient, and possessing good compressibility properties. The excipients were chosen carefully to give the appropriate dissolution rate and stability to the finished dosage form. The primary goal was to develop a stable immediate-release formulation characterized by good taste and rapid disintegration, which leads to greater absorption and high levels of the active ingredient in the systemic circulation. It has been surprisingly found that the object of the present invention is achieved by employing an effective amount of a pH-dependent excipient as a taste masking agent, that is insoluble in an acidic environment and soluble in neutral or alkaline conditions and by reducing the burning of the mucosa which occurs when diclofenac contacts the mucosa, such as tongue and mouth mucosa. To achieve the best palatability, diclofenac-free acid is selected as the preferred form of API.
[0035] Taste masking agents like, sodium starch glycolate (Primojel), sodium starch glycolate, a representative example of a cross-linked starch, is a modified starch possessing very significant disintegrating properties and is practically insoluble in organic solvents. Chemically, Primojel constitutes a low-substituted carboxymethyl starch. Sodium starch glycolate presents very good hydration capacity and very good flow properties in comparison to other super disintegrants. Further, it presents the tendency to absorb water rapidly, so it swells in a significant amount. Therefore, this rapid water absorption by sodium starch glycolate molecules leads to a significant increase in the volume of granules and further results in rapid and uniform disintegration. Sodium starch glycolate incorporated in a pharmaceutical composition facilitates the breakup or disintegration of the content of the tablet into smaller particles that dissolve more rapidly than in the absence of disintegrating agents. Sodium starch glycolate is incorporated into the composition of the present invention by external addition (extra-granular).
[0036] The effective amount of taste-masking agents has been optimized to obtain the maximum disintegration efficiency while reducing or eliminating or reducing the burning.
[0037] Additional excipients may be incorporated in the formulation to improve the physicochemical properties of the composition. Other flavor enhancers such as menthol, saccharin, or vanilla are also used to improve the taste of the tablets and limit the bitterness, and enhance the sweetness and the mouthfeel of the formulation. Moreover, the pharmaceutical compositions of the present invention may also contain one or more additional formulation excipients such as diluents, disintegrants, binders, lubricants, glidants, and flavoring agents, provided that they are compatible with the active ingredient of the composition, so that it does not interfere with it in the composition and to increase the stability of the drug and the self-life of the pharmaceutical product.
[0038] The present specification further describes the pharmaceutical development report that summarizes the development of Diclofenac Sublingual Tablets 50mg. This product is in immediate release (IR) dosage form, intended for sublingual usage, and is indicated for the treatment of primary dysmenorrhea, for relief of mild to moderate pain, for relief of the signs and symptoms of osteoarthritis, for relief of the signs and symptoms of rheumatoid arthritis, for relief of symptoms of ankylosing spondylitis and for relief of acute migraine symptoms.
[0039] The Quality target product profile (QTPP) was determined based on the properties of the drug substance and other excipients. Further, critical quality attributes (CQAs) were identified based on the safety and efficacy of the drug product which might affect the target quality of subject generic drug product.
[0040] During the development of a drug product, there were focuses on CQAs that could be impacted by a real change in drug product formulation and manufacturing process. For Diclofenac Sublingual Tablets 50 mg the CQAs were identified i.e. Assay, Content Uniformity, dissolution and Related Substances.
[0041] Diclofenac is poorly soluble in water and belongs to BCS class II active pharmaceutical ingredients, which means low solubility and high permeability compound.
[0042] Based on the literature and solubility data, the dissolution method is finalized. Risk assessment approaches were applied throughout the development of the drug product to identify potential risks in the formulation and process variables, and also to determine what studies were needed to achieve a better-quality product. By understanding the risk assessment, a control strategy is developed.
[0043] Based on the process development and understanding of CQAs, the identified risk assessments have been updated to reduce the level of risk in Diclofenac Sublingual Tablets 50 mg.
[0044] Based on the prior experience, the formulation of a direct mixing and blending process was selected for Diclofenac Sublingual Tablets 50 mg.
[0045] Based on the prior experience of similar IR dosage forms and literature, the excipients were selected for Diclofenac Sublingual Tablets 50 mg. Excipient binary mixture incompatibility was identified during the pre-formulation of a drug product. Critical material attributes were also identified during the development of a drug product.
[0046] Moreover, by applying the blend uniformity test the risk associated with the blending and lubrication step was optimized. Hence, the final blending and lubrication step did not impact the product CQAs.
[0047] During tablet compression, the acceptable range for compression speed (machine speed) was optimized and speed adjustments were made to provide accommodation for the uniformity variations in the tablets in order to achieve optimal hardness, thickness and dissolution. Scale-up principles and plans were focused on scaling from lab to pilot scale and then cGMP Pivotal scale.
[0048] The manufacturing controls are identified for CPPs at a commercial scale and their ranges were proposed. It will be qualified and continually verified during routine commercial manufacture.
[0049] Finally, we proposed a control strategy, it includes the material attributes, critical process parameters that were identified as potentially risk variables during the initial risk assessments.
[0050] Control strategy is also applied for in-process controls of the manufacturing process and finished product specifications. The process will be monitored during the lifecycle of the product and additional knowledge gained will be utilized to make adjustments to the control strategy as appropriate.
[0051] 1) Further, the present specification describes the components of the drug product.
[0052] 1.1) Drug Substance:
[0053] 1.1.1) Physico chemical Characterization of Drug substance:
[0054] Diclofenac drug substance manufactured by Amoli was used for development and optimization studies. This drug substance has been evaluated for the drug physicochemical characteristics, which may influence the performance of the drug product.
[0055] 1.1.2) Pharmacodynamics:
[0056] Diclofenac is part of the nonsteroidal anti-inflammatory category and is a weak organic acid (pKa-4.00). It is known that its main action is the ability to decrease the activity of the isoforms of the cyclooxygenase enzyme and the consequent inhibition of prostaglandin synthesis.
[0057] The following Table 1 depicts the pharmacokinetics of Diclofenac:

S. No Attribute Remarks
1 Absorption Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). Food has no significant effect on the extent of Diclofenac absorption. However, there is usually a delay in the onset of absorption of 1 to 4.5 hours and a reduction in peak plasma levels of <20%.
2 Distribution The apparent volume of distribution (V/F) of Diclofenac sodium is 1.4 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 gg/mL) achieved with recommended doses. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of Diclofenac.
3 Metabolism Five Diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'- hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy-and 5- hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.
However, Diclofenac metabolites undergo further glucuronidation and sulfation followed by biliary excretion. One Diclofenac metabolite 4'-hydroxy-diclofenac has very weak pharmacologic activity.
4 Elimination Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged Diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged Diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged Diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged Diclofenac is approximately 2 hours.
[0058] The following Table 2 depicts the pharmacokinetic parameters for Diclofenac:

Pharmacokinetic Parameters for Diclofenac - Normal Healthy Adults (20-48 yrs.)
PK Parameter Mean Coefficient of Mean Variation(%)
Absolute Bioavailability (%) [N = 7] 55 40
Tmax (hr) [N = 56] 2.3 69
Oral Clearance (CUF; mL/min) [N = 56] 582 23
Renal Clearance (% unchanged drug in urine) [N - 7] •=1
Apparent Volume of Distribution (V/F; L/kg) [N56] 1.4 58
Terminal Half-life (hr) [N -- 56] 2.3 48

[0059] The following Table 3 depicts the physical and chemical properties of Diclofenac:
[0060] 1.1.3) Drug Substance Particle Size Selection for Product Development
[0061] Particle size distribution of Diclofenac was studied and the results are tabulated below. The following Table 3 depicts the Diclofenac particle size distribution:

Batch No. % Particles passed through 40 mesh
DA/2009/0050A 98.99
DA/2103/0013A 99.65

[0062] Based on development batch data & PSD data of the various lots received from API manufacturer which has been used during development lab trials, the following particle size. The specification has been proposed for Diclofenac API to have a batch-to-batch consistency for further evaluation.
[0063] Particle size: for Diclofenac by sieve. The minimum 98% of particles should be passed through 40 mesh.
[0064] The following Table 4 depicts the physical and chemical properties of Diclofenac.
Batch No. % Particles passed through 40 mesh
DA/2009/0050A 98.99
DA/2103/0013A 99.65

[0065] The following Table 5 describes solubility:
S. No Solvent Diclofenac
Solubility (mg/mL)
1. Purified Water 14.18
2. 0.1M HCl 0.0012
3. 0.01M HCl 0.0017
4. 0.001 M HCl 0.28
5. pH 4.5 Acetate Buffer 0.0036
6. pH 6.8 Phosphate Buffer 0.67
7. pH 7.4 Phosphate Buffer 5.15

[0066] 1.1.4) POLYMORPHISM:
[0067] To study any Polymorphic changes of drug substance during the preparation of Diclofenac Sublingual Tablets 50mg formulation as well as during the stability storage at 40 °C ± 2°C / 75% RH ± 5% RH, the samples of development batches of Diclofenac Sublingual Tablets 50 mg were analyzed by X-Ray powder diffraction spectroscopy, initially and after 3 months of stability storage at 40°C ± 2°C 175 % RH + 5% RH.
[0068] The X-Ray powder diffraction pattern of Diclofenac Sublingual Tablets 50mg, exhibits the diffraction peaks at 2-theta values, which are characteristic of Diclofenac drug substance, thereby indicating no change in the Polymorphic form of Diclofenac drug substance during the process of tablets formulation as well as after 3 months of stability storage at 25°C/60 %RH % and 40°C/75 %RH % RH.
[0069] 1.1.5) Biological Properties:
[0070] Bio-pharmaceutics Classification: Diclofenac has low solubility within the studied pH range. Quality Target Product Profile for the Product.
[0071] Based on the drug substance's characterization and pharmacokinetic (PK) characteristics a quality target product profile (QTPP) has been identified. The QTPP for Diclofenac Sublingual Tablets 50mg was determined and identified the CQAs role on QTPP of drug product. QTPP of drug product are tabulated below:
[0072] The following Table 6 depicts quality target product profile (QTPP) for Diclofenac Sublingual Tablets 50 mg:
QTPP Element Target Justification
Dosage form Tablet Patient Compliance
Dosage design Immediate release tablet Immediate release design needed to meet customer requirement.
Route of administration Oral Patient Compliance
Dosage strength 50mg As per customer requirement.

Stability At least 24-month shelf-life at control room temperature Considering the minimum shelf-life for pharmaceutical products.
Pharmacokinetics Immediate release dosage form. Needed to ensure rapid onset and efficacy.

Drug product quality attributes Physical Attributes Meeting the compendial or other applicable (quality) standards (i.e., identity, assay, purity, and quality.)
Identification
Assay
Uniformity of dosage units
Disintegration time
Related Substances
Dissolution
Water content
Packing Suitable for drug product To ensure stability in the primary pack.

[0073] The above table summarizes the Quality attributes of Diclofenac Sublingual Tablets 50mg along with drug product critical quality attribute (CQAs). For this product, Assay, Uniformity of dosage units (by Content Uniformity), Dissolution and Related substances are identified as the attributes that have potential impact on the formulation and/or manufacturing process variables. Therefore, these attributes will be investigated and elaborated in detail in subsequent developmental studies. On the other side, other attributes like identity, water content, and disintegration time which are unlikely to be impacted by formulation and/or process will not be elaborated or discussed in detail in the pharmaceutical development report.
[0074] The following Table 7 depicts the initial risk assessment on drug product CQA:
Drug Product CQA Level of risk Rationale
Dissolution Medium Diclofenac API being a low soluble API and Diclofenac sublingual Tablets dissolution will be critical and therefore, the risk was assigned as medium. Also dissolution is important CQA it is evaluated for its impact on drug product.
Physical parameters of tablets Low Diclofenac API is almost 20.8% in Diclofenac sublingual Tablets and the process is direct mixing procedure so there is no impact on physical parameters of tablet. Hence the risk was assigned as low.
Low Broadly acceptable risk. No further investigation is needed.
Medium Risk is acceptable. Further investigation may be needed in order to reduce the risk.
High Risk is unacceptable. Further investigation is needed to reduce the risk.
[0075] The formulation strategy adopted for the development of Diclofenac sublingual Tablets 50 mg was direct mixing and hence there is no impact on the physical parameters of tablets, hence the risk was assigned as low.
[0076] Based on the above risk assessment, the Dissolution of tablets was assigned as medium risk and further subject to detailed evaluation.
[0077] 1.2) Active Pharmaceutical Ingredient Characterization
[0078] Diclofenac (Diclofenac free acid) API was sourced from M/s. Amoli Organics Private Limited for the development of Diclofenac Sublingual Tablets 50mg.
[0079] The following Table 8 depicts the analytical results of the active pharmaceutical ingredient:
Material Name: Diclofenac (Diclofenac Free Acid) B. No: DA/2103/0013A
Mfg date: Mar-2021 Expiry date: Feb-2026
Test Specification Results
Description A White or slight yellowish crystalline powder Conform
Identification
A) By IR Spectroscopy The sample spectrum and the reference spectrum are consistent in all essential spectral details. Conform
B) By HPLC The HPLC retention time of the main peak is within 0.5 minutes of the main peak for the refrence standard injection. Conform
Related substances by HPLC
(%)
Impurity A
Unknown Impurity
Total Impurities

Not more than 1.0
Not more than 0.10
Not more than 0.3

0.01
0.05
0.13
Heavy Metals
(ppm) Not more than 10 Less than 10
Residue on Ignition
(%w/w) Not more than 0.1 0.04
Loss on Drying
(%w/w) Not more than 0.5 0.20
Assay
(%w/w, calculated on dried basis) Not less than 98.5 and Not more than102.0 101.9
Additional Inhouse test
Particle size
(%, By sieve) Minimum 98% particles passing through 40 mesh 98.7
Solubility Sparingly soluble in methanol, slightly soluble in chloroform Complies
Acidity or Alkalinity
(pH of 1% w/v suspension in water) Between 4.0 and 6.5 5.4
Light absorbance
(2%w/v solution in methanol/440nm/4cm) Not more than 0.06 0.027
Residual solvents by GC
(ppm)
Isopropyl Alcohol
Toluene

Not more than 5000
Not more than 805

4245
805
[0080] The drug substance complies as per the above predetermined vendor specifications for Diclofenac (Diclofenac free acid). The drug substance complied with ICH recommended limits for residual solvents.
[0081] Excipients:
[0082] Based on the Pharmaceutical product experience the below excipients are selected for the development of Diclofenac Sublingual Tablets 50mg.
[0083] The following Table 9 depicts excipients and its manufacturer details:
S.No. Excipient Name Manufactured by
1 Mannitol (Pearlitol SD 200) Roquette
2 Art. cherry flavor Virginia Dare
3 Sodium starch glycolate (Type A) (Primojel) Gangwal Chemicals Pvt. Ltd.,
4 Croscarmellose sodium Dupont
5 Microcrystalline Cellulose (Avicel PH-112) Dupont
6 Aspartame (Aminosweet Power) Ajinomoto Co. Inc.,
7 Colloidal silicon dioxide (Aerosil) ® 200 Pharma Evonik
8 Sodium Stearyl Fumarate Alcedo
[0084] The following Table 9.1 depicts the specification of Mannitol (Pearlitol SD 200):
S.No. Test Limit
1 Description A white, crystalline powder or free- flowing granules.
2 Identification
A) By IR The transmission minima or absorption maxima in the spectrum obtained with the substance recorded, as KBr pellet should correspond in position and relative size to those in the spectrum obtained with that of standard.
B) By Chemical A Clear solution is should be obtained which remains clear on the further addition of sodium hydroxide solution.
C) By Chemical A Pink colour is should be produced.
D) Melting Point (°C) Between 165 and 170
3 Appearance of Solution Solution should be clear and colourless.
4 Acidity or Alkalinity Not more than 0.2 ml of 0.01M Sodium hydroxide is required to change the colour of the solution to pink.
5 Specific Optical Rotation
([?] 20D C=8, on dried substance) Between +23.0° and +25.0°
6 Arsenic (ppm) Not more than 2
7 Chlorides (ppm) Not more than 50
8 Sulphates (ppm) Not more than 100
9 Reducing Sugars Not less than 12.8 ml of 0.05M sodium thiosulphate is required.
10 Sorbitol (By TLC) Any spot corresponding to sorbitol in the chromatogram obtained with the test solution is not more intense than the spot in the chromatogram obtained with the reference solution.
11 Sulphated Ash (%w/w) Not more than 0.1
12 Loss on Drying (% w/w) Not more than 0.5
13 Assay
(% w/w, By HPLC, on dried substance) Not less than 97.0 and Not more than102.0
[0085] The following Table 9.2 depicts the specification of Artificial cherry flavor:
S.No. Test Limit
1 Description Off white powder.
2 Water (% W/W, by KF) Not more than 8.0
3 Particle Size (% w/w, By Sieve Analysis) Not less than 99.00
4 Microbial Enumeration tests and
Test for Specified Micro Organisms
(Cfu/g)
TAMC Not more than 100
TYMC Not more than 10
[0086] The following Table 9.3 depicts the specification of Sodium starch glycolate (Type A) (Primojel):
S.No. Test Limit
1 Description A Very fine, white or off white, free flowing powder.
2 Identification
A) By IR The IR Spectrum of the sample dispersed in KBr should be concordant with IR spectrum of the Sodium starch Glycolate RS/WS
B) By Chemical A Dark blue colour should be Produced.
C) By Chemical The Solution obtained in the test for heavy metal should give the reaction of sodium salt.
3 pH Type A between 5.5 and 7.5.
4 Heavy Metals NMT 20ppm.
5 Iron (ppm) Maximum 20ppm
6 Sodium Chloride (% w/w) Maximum 10.0
7 Loss on Drying (%w/w) Maximum 10.0
8 Sodium Glyclate (% w/w) The absorbance of the resulting solution at the maximum at about 540nm using water as blank is not more than that of a standard solution prepared.
9 Assay 2.8 to 4.5 of sodium
10 Microbial Enumeration
a) Total Aerobic Microbial Count Not more than 1000 cfu/gm
b) Total Yeast and Mold Count Not more than 100 cfu/gm
c) Escherichia coli It should be Absent
d) Salmonella Abony It should be Absent
e) Pseudomonas aeruginosa It should be Absent
f) Staphylococcus aureus It should be Absent
[0087] The following Table 9.4 depicts the specification of croscarmellose sodium:
S.No. Test Limit
1 Description A white or greyish-white powder.
2 Identification
A) By Chemical The substance under examination absorbs the methylene blue and settles as a blue fibrous mass.
B) By Chemical A reddish violate colour develops at the interface.
C) Sodium It gives positive reaction.
3 pH 5.0 – 7.0
4 Degree of Substitution Between 0.60 to 0.85
5 Sodium Chloride and Sodium Glycollate Not more than 0.5%
6 Water Soluble Ssubstances Not more than 10%
7 Heavy Metals Not more than 10 ppm
8 Settling Volume (mL) Between 10.0 to 30.0
9 Microbial Contamination
g) Total Aerobic Microbial Count NMT 1000 cfu/g
h) Total Yeast and Mold Count NMT 100 cfu/g
i) Escherichia coli It should be Absent
j) Salmonella Abony It should be Absent
k) Pseudomonas aeruginosa It should be Absent
l) Staphylococcus aureus It should be Absent
10 Sulphated ash % Between 14.0 to 28.0
11 Loss on drying NMT 10 %
[0088] The following table 9.5 depicts the specification of Microcrystalline Cellulose (Avicel PH-112):
S. No. Test Limit
1 Description A fine or granular, white or almost white powder.
2 Identification
A) By Chemical A red colour should be produced.
B) By Chemical A blue-purple colour should be produced.
C) By Chemical A white, opaque, bubble-free dispersion is obtained that does not produce a supernatant liquid.
3 pH Between 5.0 to 7.5
4 Starch and Dextrins No blue or brownish colour is produced.
5 Organic Impurities No red colour should be produced.
6 Water soluble substance NMT 0.2%
7 Arsenic NMT 2 ppm
8 Heavy Metals NMT 10 ppm
9 Sulphated ash NMT 0.2 %
10 Loss on drying NMT 6 %
11 Assay NLT 97.0 % and NMT 102.0 %
[0089] The following Table 9.6 depicts the specification of Aspartame (Aminosweet Power):
S. No. Test Limit
1 Description A white, Crystalline powder.
2 Identification
A) By IR The IR Spectrum of sample recorded as KBr pellet should be concordant with similarly recorded spectrum of standard.
A) By UV Shows absorption maxima should be at about 247 nm, 252 nm, 258 nm and 264nm.
3 pH About 5.0
4 Specific Optical Rotation (°) +14.5 to +16.5
5 Light Absorption Not more than 0.022
6 Benzyl-3, 6-dioxo-2-piperazineacetic acid.
(By HPLC, % ) Not more than 1.5
7 Other Related Substances
(By HPLC, %) Not more than 2.0
8 Arsenic (ppm) Not more than 3
9 Heavy metals (ppm) Not more than 10
9 Sulfated Ash (% w/w) Not more than 0.2
10 Loss on Drying Not more than 4.5
11 Assay (% w/w, By Titrimetry, on anhydrous basis) Not less than 98.0 and Not more than102.0.
[0090] The following Table 9.7 depicts the specification of Colloidal silicon dioxide (Aerosil) ® 200 Pharma:
S. No. Test Limit
1 Description A light, fine, white amorphous powder.
2 Identification
A) By Chemical It gives the reaction of silicates.
3 pH 3.5 to 5.5
4 Arsenic (ppm) Not more than 8
5 Heavy metals (ppm) Not more than 25
6 Chlorides (ppm) Not more than 250
7 Loss on Ignition (% w/w) Not more than 5.0
8 Assay (% w/w in the ignite basis) Not less than 99.0 and Not more than 100.5
[0091] The following Table 9.8 depicts the specification of Sodium Stearyl Fumarate USNF:
S. No. Test Limit
1 Description Fine, white powder.
2 Solubility Slightly soluble in methanol, practically insoluble in water.
3 Identification
A) By IR The IR Spectrum of sample recorded as KBr pellet should be concordant with similarly recorded spectrum of standard.
4 Water (%w/w) Not more than 5.0
5 Lead (%w/w) Not more than 0.001
6 Saponification Value
(On anhydrous basis) Between 142.2 and 146.0
7 Limit of Sodium Stearyl Maleate and Stearyl Alcohol (By TLC. % )
Sodium Stearyl Maleate Not more than 0.25
Stearyl Alcohol Not more than 0.5
8 Assay
(% w/w, By Titrimetry, on anhydrous basis) Not less than 99.0 and Not more than101.5.
9 Residual Solvent
(By GC, µg/g)
a) Acetone Not more than 500
b) Toluene Not more than 890
[0092] The following Table 10 depicts Critical and non-critical quality attributes of Diclofenac Sublingual Tablets 50mg.

Drug Product Quality Attributes Target Is this CQA Justification of Criticality
Physical attributes Appearance (Color and Shape) Color and shape conforming to description. No visual tablet defects observed. No Color, shape and appearance are not directly linked to safety and efficacy. Therefore, they are not critical. The target is set to ensure patient acceptability. As per customer requirement.
Size As per customer requirement. As per customer requirement.
Friability NMT 1% m/m No Friability is a routine test per compendial requirements for tablets. A target of NMT 1.0% m/m of mean mass loss assures a low impact on patient safety and efficacy and minimizes customer complaints
Identification Drug substance identification should match with reference standard. No Though identification is critical for safety and efficacy, this CQA can be effectively controlled by the quality management system and will be monitored at drug product release. Formulation and process variables do not impact identity. Therefore, this CQA will not be discussed during formulation and process development.
Assay 100.0 % of label claim Yes Assay variability will affect safety and efficacy. Process variables may affect the assay of the drug product. Thus, assay will be evaluated throughout product and process development.
Uniformity of dosage units Acceptance Value
NMT 15.0 Yes Variability in uniformity of dosage units will affect safety and efficacy. Both formulation and process variables impact uniformity of dosage units, so this CQA will be evaluated throughout product and process development.
Related Substances As per the compendial requirement and Formulation Yes Related Substances can impact safety and must be controlled based on compendial/ICH requirements. The limit for total impurities is also based on Innovator and trend data. Formulation and process variables can impact Related Substances. Therefore, Related Substances will be assessed during product and process development.
Dissolution Not less than 80 % (Q) of the labeled amount of Diclofenac is dissolved in 15minutes. Yes Failure to meet the dissolution specification can impact bioavailability. Both formulation and process variables affect the dissolution profile. This CQA will be investigated throughout formulation and process development.
Water by KF (%) Not more than 8.5 No Generally, water may affect degradation and can be a potential CQA. Based on the development trial it was concluded that the water content has not substantial impact on formulation in presence of inherent moisture in the excipients.
Disintegration Time (min.) Not More Than 5 Yes Both formulation and process variables affect the Disintegration time. This CQA will be investigated throughout formulation and process development.

[0093] During pharmaceutical development, all attributes in the QTPP are monitored. The above drug product CQAs were identified for explicit tracking in risk assessment: Assay, Related Substances / Impurities, Content Uniformity, Dissolution. The criteria for inclusion of all above tests for CQAs were identified and monitored during formulation development.
[0094] 1.3) Risk Assessment of Drug Substance Attributes
[0095] A risk assessment was performed to evaluate the impact of drug substance attributes on the drug product CQAs. Based upon the physicochemical and biological properties of the drug substance, the initial risk of drug substance was investigated and also evaluated their impact on the drug product CQAs, same is tabulated below.
[0096] The following Table 11 depicts the initial risk assessment of the drug substance attributes:

DRUG SUBSTANCE ATTRIBUTES
Drug Product CQA Particle
Size Polymorphism
(Solid State
Fn Solubility Chemical
Stability Moisture content Residual
Solvents Process
impurities Flow properties
Assay Low Low Low
_ Low Low Low Low Low
Uniformity of dosage units Low Low Low Low Low Low Low Low
Dissolution Medium Low Medium Low Low Low Low Low
Related Substances Low Low Low Medium Low Low Low Low
Medium: Risk is acceptable. Further investigation may be needed in order to reduce the risk.
Low: Broadly acceptable risk. No further investigation is needed.

[0097] The following Table 12 depicts justification for the initial risk assessment of the drug substance attributes:
Drug Substance attributes Drug Product CQAs Justification
Particle Size Assay A small particle size and wide PSD may adversely impact blend homogeneity and flowability. In extreme cases, poor flow ability and segregation may cause an assay problem. However, as the API PSD was well controlled with tighter specifications. Therefore, risk is low.
UOD Particle size distribution has a direct impact on drug substance flow ability and segregation during manufacturing process and ultimately on Uniformity of dosage units. However, as the API PSD was well controlled with tighter specifications Therefore risk is low.
Dissolution PSD has role in the intrinsic dissolution of API and hence dissolution of dosage forms. Therefore, risk is medium.
Related Substances Diclofenac is relatively stable molecule therefore impact of drug substance PSD on Related Substances is low.
Polymorphism
(Solid State Form) Assay Different polymorphic forms of the drug substance have different solubility and can impact tablet dissolution. However, there is no polymorphic conversion was occurred for Diclofenac Sublingual Tablets 5mg during the formulation development and in the stability period. Therefore the risk is Low.
UOD
Dissolution
Related Substances
Solubility Assay Solubility does not affect tablet assay, uniformity of dosage units and Related Substances, Thus, the risk is low.
UOD
Related Substances
Dissolution Diclofenac belongs to low soluble drug substance. Therefore the risk is Medium.
Chemical Stability Assay The drug substance is substantially less sensitive to degradation at stress conditions. Therefore, risk is low.
UOD Uniformity of dosage units is mainly impacted by blend flow ability, blend uniformity and tablet weight variation. Uniformity of dosage units is unrelated to drug substance chemical stability. The risk is low.
Dissolution There is no direct impact of drug substance stability on dissolution. The risk is low.
Related Substances The drug substance is substantially less sensitive to degradation at stress conditions. However, drug substance impurities are linked to the final product impurities. Therefore, risk is medium.
Moisture content Assay Moisture level is unlikely to impact assay, uniformity of dosage units and dissolution. The risk is low.
UOD
Dissolution
Related Substances Moisture level is unlikely to impact degradation of Diclofenac drug substance. The risk is low.
Residual Solvents Assay Residual solvents are controlled in the drug substance specification and comply with ICHQ3C. The risk is low.
UOD
Dissolution
Related Substances
Process impurities Assay Total impurities are controlled in the drug substance specification. Within this low range, process impurities are unlikely to impact Assay, Uniformity of dosage units and dissolution. The risk is low.
UOD
Dissolution
Related Substances During the excipient compatibility study, no incompatibility was observed. The risk is low.
Flow properties Assay Diclofenac has poor flow properties. However, the manufacturing process is by granulation that improves flow property. Therefore, the risk is low for Assay.
UOD Diclofenac has poor flow properties. However, the manufacturing process is by granulation that improves flow property Therefore, the risk is low for uniformity of dosage units.
Dissolution The flow ability of the drug substance is not related to its degradation pathway or solubility. Therefore, the risk is low.
Related Substances
[0098] 1.4) Drug Excipient Compatibility Studies:
[0099] The objective of the study was to determine the interaction of Diclofenac with Excipients to be used in the formulation. Open vials containing drug and excipient blends were incubated at pierced vials at 40°C/75% RH for a period of 1 month and observed for change in physical and chemical attributes. Controlled samples were kept at room temperature conditions (25°C). The observations are recorded in the table below.
[00100] The following Table 13 depicts physical compatibility:

S. No Composition details Binary Mixture
Drug : Excipient
Ratio Description
Initial 25?C/60% RH 40?C/75% RH
1 month 1 month
1 SP-DSL_21-001 (API) 1 : 0 NCC NCC NCC
2 SP-DSL_21-001+Mannitol (Pearlitol SD 200) 1 : 2 NCC NCC NCC
3 SP-DSL-21-001 + Art. Cherry flavor 1 : 2 NCC NCC NCC
4 SP-DSL-21-001+Sodium starch glycolate (Type A) (Primojel) 1 : 2 NCC NCC NCC
5 SP-DSL-21-001+ Croscarmellose sodium 1 : 2 NCC NCC NCC
6 SP-DSL-21-001+ Microcrystalline sodium (PH – 112) 1 : 2 NCC NCC NCC
7 SP-DSL-21-001+ Aspartame (Amino sweet powder) 1 : 2 NCC NCC NCC
8 SP-DSL-21-001+ Colloidal Silicon dioxide (Aerosil @ 200 Pharma) 1 : 2 NCC NCC NCC
9 SP-DSL-21-001+ Sodium Stearyl Fumarate 1 : 2 NCC NCC NCC
10 SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor 1 : 2 NCC NCC NCC
11 SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) 1 : 2 NCC NCC NCC
12 SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium 1 : 2 NCC NCC NCC
13 SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium + Microcrystalline Cellulose (PH-112) 1 : 2 NCC NCC NCC
14 SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium + Microcrystalline Cellulose (PH-112) + Aspartame (Amino sweet Powder) 1 : 2 NCC NCC NCC
15 SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium + Microcrystalline Cellulose (Avicel PH-112) + Aspartame (Amino sweet Powder) + Colloidal Silicon dioxide (Aerosil @200 Pharma) 1 : 2 NCC NCC NCC
16 SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium + Microcrystalline Cellulose (Avicel PH-112) + Aspartame (Amino sweet Powder) + Colloidal Silicon dioxide (Aerosil @200 Pharma)+ Sodium Steryl Fumarate 1 : 2 NCC NCC NCC
NCC– No Characteristic Change
[00101] Tables 14 depicts chemical compatibility: related substances:
Sample - 1
Drug: Excipients Ratio SP-DSL-21-001 (API) – 1:0
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.01 0.02 0.10
1 Month 25°C/60% RH 0.01 0.01 0.02 0.07
1 Month 40°C/75% RH 0.01 0.02 0.02 0.06

Sample - 2
Drug: Excipients Ratio SP-DSL_21-001+Mannitol (Pearlitol SD 200) – 1: 2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 246.88
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.02 0.02 0.10
1 Month 25°C/60% RH 0.01 0.01 0.02 0.08
1 Month 40°C/75% RH 0.02 0.01 0.02 0.07

Sample - 3
Drug: Excipients Ratio SP-DSL-21-001 + Art. Cherry flavor – 1: 2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 30
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial Not Detected Not Detected 0.02 0.02
1 Month 25°C/60% RH Not Detected 0.01 0.02 0.06
1 Month 40°C/75% RH 0.02 0.02 0.02 0.10

Sample - 4
Drug: Excipients Ratio SP-DSL-21-001+Sodium starch glycolate (Type A) (Primojel) – 1: 2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 30
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.01 0.02 0.08
1 Month 25°C/60% RH 0.01 0.02 0.02 0.07
1 Month 40°C/75% RH 0.02 0.01 0.02 0.06

Sample - 5
Drug: Excipients Ratio SP-DSL-21-001+ Croscarmellose sodium – 1: 2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 20
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.02 0.02 0.08
1 Month 25°C/60% RH 0.01 0.02 0.02 0.08
1 Month 40°C/75% RH 0.03 0.01 0.01 0.06

Sample - 6
Drug: Excipients Ratio SP-DSL-21-001+ Microcrystalline sodium (Avicel PH – 112) – 1: 2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 30
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.01 0.02 0.07
1 Month 25°C/60% RH 0.01 0.02 0.02 0.11
1 Month 40°C/75% RH 0.02 0.02 0.02 0.06

Sample - 7
Drug: Excipients Ratio SP-DSL-21-001+ Aspartame (Amino sweet powder) – 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 6
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.01 0.02 0.07
1 Month 25°C/60% RH 0.01 0.01 0.02 0.07
1 Month 40°C/75% RH 0.02 0.01 0.02 0.06

Sample - 8
Drug: Excipients Ratio SP-DSL-21-001+ Colloidal Silicon dioxide (Aerosil @ 200 Pharma)
– 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 8
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.02 0.02 0.07
1 Month 25°C/60% RH 0.01 0.01 0.02 0.08
1 Month 40°C/75% RH 0.03 0.01 0.02 0.06

Sample - 9
Drug: Excipients Ratio SP-DSL-21-001+ Sodium Stearyl Fumarate – 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 16
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.02 0.02 0.10
1 Month 25°C/60% RH 0.01 0.01 0.02 0.10
1 Month 40°C/75% RH 0.02 0.01 0.01 0.06

Sample - 10
Drug: Excipients Ratio SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor
– 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 246.88 + 30
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.02 0.02 0.09
1 Month 25°C/60% RH 0.01 0.02 0.02 0.08
1 Month 40°C/75% RH 0.02 0.01 0.01 0.05

Sample - 11
Drug: Excipients Ratio SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) – 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 246.88 + 30 + 30
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.02 0.02 0.10
1 Month 25°C/60% RH 0.01 0.02 0.02 0.09
1 Month 40°C/75% RH 0.02 0.02 0.03 0.09

Sample - 12
Drug: Excipients Ratio SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium – 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 246.88 + 30 + 30 + 20
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial Not Detected 0.02 0.02 0.05
1 Month 25°C/60% RH 0.01 0.02 0.02 0.08
1 Month 40°C/75% RH 0.01 0.03 0.02 0.07

Sample - 13
Drug: Excipients Ratio SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium + Microcrystalline Cellulose (PH-112) – 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 246.88 + 30 + 30 + 20 + 30
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.01 0.02 0.08
1 Month 25°C/60% RH 0.01 0.01 0.01 0.06
1 Month 40°C/75% RH 0.01 0.02 0.01 0.06

Sample - 14
Drug: Excipients Ratio SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium + Microcrystalline Cellulose (PH-112) + Aspartame (Amino sweet Powder) – 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 246.88 + 30 + 30 + 20 + 30 + 6
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.02 0.01 0.07
1 Month 25°C/60% RH 0.01 0.02 0.02 0.06
1 Month 40°C/75% RH 0.01 0.02 0.01 0.07

Sample - 15
Drug: Excipients Ratio SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium + Microcrystalline Cellulose (PH-112) + Aspartame (Amino sweet Powder) + Colloidal Silicon dioxide (Aerosil @200 Pharma) – 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 246.88 + 30 + 30 + 20 + 30 + 6 + 8
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.02 0.01 0.05
1 Month 25°C/60% RH 0.01 0.01 0.03 0.08
1 Month 40°C/75% RH 0.01 0.01 0.01 0.05

Sample - 16
Drug: Excipients Ratio SP-DSL-21-001+ Mannitol (Pearlitol D 200) + Art. Cherry flavor + Sodium starch glycolate (Type A) (Primojel) + Croscarmellose sodium + Microcrystalline Cellulose (Avicel PH-112) + Aspartame (Amino sweet Powder) + Colloidal Silicon dioxide (Aerosil @200 Pharma) + Sodium Steryl Fumarate – 1:2
Storage Condition Initial, 25°C/60%RH and 40°C/75% RH
Qty of the Blend (mg) 46.50 + 246.88 + 30 + 30 + 20 + 30 + 6 + 8 + 16
RESULTS
Condition Impurity-A
(% w/w) Impurity-F
(% w/w) Any unspecified degradation product (% w/w) Total degradation products
(% w/w)
Initial 0.01 0.02 0.01 0.07
1 Month 25°C/60% RH 0.01 0.02 0.02 0.08
1 Month 40°C/75% RH 0.01 0.01 0.02 0.10

[00102] Hence, there is no drastic change in impurity profiles were observed during compatibility studies with excipients, it may be inferred that Diclofenac is compatible with the excipients used in the study and therefore above-mentioned excipients may be used in the formulation of Diclofenac Sublingual Tablets 50 mg.
[00103] 1.5) Drug Product
[00104] 1.5.1) Dissolution Method Development:
[00105] The following Table 15 depicts the dissolution profiles of Diclofenac ssublingual tablets 50mg:
In 500 mL of 0.1N HCl in Paddle at 50 RPM
B.No.: DSL-21-032
Time (min) Individual Units Avg %RSD
5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
10 1.7 1.0 1.0 0.9 0.8 0.7 1.0 35.5
15 1.2 1.1 1.6 1.3 1.3 1.2 1.3 13.4
20 1.5 1.6 1.8 1.5 1.6 1.7 1.6 7.2

In 500 mL of pH 4.5 Acetate Buffer in Paddle at 50 RPM
B.No.: DSL-21-032
Time (min) Individual Units Avg %RSD
5 1.3 1.4 1.3 1.3 1.5 2.9 1.6 39.20
10 4.1 4.3 4.3 4.2 4.1 4.3 4.2 2.33
15 6.6 6.6 6.6 6.7 7.0 6.6 6.7 2.40
20 8.1 9.5 8.3 8.6 8.1 8.3 8.5 6.26

In 500 mL of pH 6.8 Phosphate Buffer in Paddle at 50 RPM
B.No.: DSL-21-032
Time (min} Individual Units Avg %RSD
5 89.8 92.3 91.1 89.8 92.5 90.9 91 1.28
10 101.9 100.0 98.5 101.9 100.2 98.4 100 1.53
15 101.6 103.8 101.2 101.6 101.4 100.7 102 1.50
20 101.2 100.9 100.5 101.1 100.8 100.1 101 0.41

In 500 mL of pH 7.5 Phosphate Buffer in Paddle at 50 RPM
1
B.No.: DSL-21-032
Time
(min) Individual Units Avg %RSD
5 86.6 94.5 82.5 89.0 95.0 101.1 91 7.37
10 94.9 99.1 97.0 95.0 102.7 104.7 99 4.10
15 100.1 103.2 100.1 99.5 102.7 106.1 102 2.48
20 102.4 100.0 99.7 98.4 101.7 104.1 101 2.07

[00106] For better dissolution rate during stability of product, have been developed the dissolution method by using the dissolution medium pH 6.8 Phosphate Buffer with 0.1% SLS.

In 500 mL of pH 6.8 Phosphate Buffer with 0.1% SLS in Paddle at 50 RPM
B.No.: DSL-21-032
Time
(min) Individual Units
_ Avg %RSD
5 79.5 79.4 79.4 79.3 79.2 79.6 79 0.18
10 95.2 95.5 95.7 95.7 95.5 95.5 96 0.19
15 95.7 95.8 96.1 95.9 95.5 96.0 95 0.23
20 105.9 105.7 106.1 106.1 105.9 106.0 106 0.14
[00107] 1.5.2) Justification for the Selection of the Dissolution Volume:
[00108] Based on the solubility of the drug substance, sink conditions can be easily achieved using 500 mL of dissolution medium and hence the volume of dissolution medium was fixed as 500 mL to maintain minimum possible concentration gradient effect during release.
[00109] 1.5.3) Justification for the Selection of the Dissolution Apparatus:
[00110] The dissolution apparatus selected is Paddle, which is commonly used for dissolution testing of conventional release dosage forms.
[00111] 1.5.4) Justification for the Selection of Agitation:
[00112] As per the general requirement of the Indian Pharmacopeial guidelines for a Paddle apparatus 50 RPM was recommended as a part of the development activity, the dissolution of Diclofenac Sublingual Tablets 50 mg was studied at 50 RPM.
[00113] 1.5.5) Justification for the Selection of the Dissolution Medium: Saturation solubility of Diclofenac drug substance in aqueous solutions with different pH has been determined. It is evident from the solubility data that Diclofenac drug substance is having High solubility in pH 7.4 phosphate buffer over pH 1.2 to 7.5 range studied.
[00114] 1.6) Formulation development:
[00115] Based upon literature search, drug substance details & excipients details development batches of Diclofenac Sublingual Tablets 50 mg was initiated and the formulation strategy adopted for the development of Diclofenac Sublingual Tablets 50 mg was direct mixing and blending process. The composition and manufacturing process are captured in the below sections.
[00116] The following Table 16 depicts unit formula:
S. No. Ingredients Quantity per unit
Batch No.: DSL-21-06
1 Diclofenac 50.00
2 Mannitol 150.00
3 Polacrilin Potassium 10.00
4 Crospovidone 10.00
5 Colloidal silicon dioxide 10.00
6 Aspartame 10.00
7 Microcrystalline Cellulose (Avicel PH-112) 30.00
8 Orange Flavor 10.00
9 Sodium Stearyl Fumarate 10.00
Table Weight 290.00
[00117] 2.0) The present specification further describes brief manufacturing process
[00118] 2.1) Sifting:
[00119] 2.1.1) Sift together Diclofenac Sodium, Mannitol, Orange Flavor and Aspartame through 250pm sieve (ASTM mesh no #60).
[00120] 2.1.2) Cosift Step 2.1.1 with Microcrystalline Cellulose through 4251.tm sieve (ASTM mesh no # 40).
[00121] 2.1.3) Cosift Step 2.1.2 with Crospovidone through 425p. sieve (ASTM mesh no # 40).
[00122] 2.1.4) Cosift Step 2.1.3 with Polacrilin Potassium through 4251.1m sieve (ASTM mesh no # 40).
[00123] 2.1.5) Sift Colloidal silicon dioxide USNF (Aerosil 0 200 Pharma) through 425pm sieve (ASTM mesh no # 40).
[00124] 2.1.6) Sift Sodium stearyl fumarate through 250pm sieve (ASTM mesh no # 60).
[00125] 2.2) Mixing: Load the material of step no 2.1.4 into suitable blender and blend for a period of 15 minutes.
[00126] 2.3) Pre-Lubrication: Add the material of step 2.1.5 to the blend of step 2.2 and blend for a period of 5 minutes.
[00127] 2.4) Lubrication
[00128] 2.4.1) Load the sifted material of step no 2.1.6 into the blend of step no 2.3 and blend for a period of 5 minutes.
[00129] 2.4.2) If unloaded store the Lubricated blend in suitable air tight container lined with double polythene bags kept in triple laminated Aluminum bags followed by sealing. Further the blend was evaluated for the physical parameters of the tablets, the details as mentioned below:
[00130] The present Table 17 further describes compression parameters:
Parameter Development Batch
Batch No.: DSL-21-06
Tooling 8.70 X 8.50 mm, Heart shaped, convex, embossed
with 'DF' on upper punch and embossed with '50'
on lower punch.
Tablet description White to off-white, Heart shaped, biconvex,
uncoated tablets debossed with `DF' on one side
and '50' on other side.
Average weight (mg) 288 — 294
Uniformity of weight -1.5 to 2.0% of target weight
Hardness (1Cp) 4.1 — 6.1
Thickness (mm) 4.46 — 4.48
Disintegration Time (sec) 58
Friability (%w/w) 0.08
[00131] Inference and Conclusion:
[00132] Physical parameters of Diclofenac Sublingual Tablets 50 mg was found satisfactory, but the taste and flavor was not satisfactory and further the evaluation was done as per the below changes and the composition and manufacturing process details as below.
[00133] The following table Table 18 depicts unit formula:

S.No. Ingredients: Quantity per Unit
Batch No.: DSL-21-08
1 Diclofenac Sodium 50.00
2 Mannitol 130.00
3 Polacrilin 20.00
4 Crospovidone 20.00
5 Colloidal silicon dioxide 10.00
6 Aspartame 15.00
7 Microcrystalline Cellulose (Avicel PH-112) 25.00
8 Orange Flavor 15.00
9 Sodium Stearyl Fumarate
r 5.00
Tablet Weight 290.00

[00134] 3.0) Brief manufacturing process:
[00135] 3.1) Sifting
[00136] 3.1.1) Sift together Diclofenac Sodium, Mannitol. Orange Flavor and Aspartame through 250p.m sieve (ASTM mesh no #60).
[00137] 3.1.2) Cosift Step 3.1.1 with Microcrystalline Cellulose through 4251.1m sieve (ASTM mesh no # 40).
[00138] 3.1.3) Cosift Step 3.1.2 with Crospovidone through 42511 sieve (ASTM mesh no 14 40). 3.1.4 Cosift Step 3.1.3 with Polacrilin Potassium through 425gm sieve (ASTM mesh no # 40).
[00139] 3.1.5) Sift Colloidal silicon dioxide USNF (Aerosil ® 200 Pharma) through 425pm sieve (ASTM mesh no # 40).
[00140] 3.1.6) Sift Sodium stearyl fumarate through 250pm sieve (ASTM mesh no # 60).
[00141] 3.2) Mixing: Load the material of step no 3.1.4 into suitable blender and blend for a period of 15 minutes.
[00142] 3.3) Pre-Lubrication: Add the material of step 3.1.5 to the blend of step 3.2 and blend for a period of 5 minutes.
[00143] 3.4) Lubrication
[00144] 3.4.1) Load the sifted material of step no 3.1.6 into the blend of step no 3.3 and blend for a period of 5 minutes.
[00145] 3.4.2) If unloaded store the Lubricated blend in a suitable airtight container lined with double polythene bags kept in triple-laminated aluminium bags followed by sealing. Further, the blend was evaluated for the physical parameters of the tablets, the details as mentioned below:
[00146] The following table 19 depicts compression parameters:

Parameter Development Batch
Batch No.: DSL-21-O8
Tooling 8.70 X 8.50 mm, Heart shaped, standard convex,
embossed with 'DF' on upper punch and embossed
with '50' on lower punch.
Tablet description White to off-white, Heart shaped, biconvex,
uncoated tablets debossed with 'DF' on one side
and '50' on other side.
Average weight (mg) 287 — 293
Uniformity of weight -1.6 to 2.2% of target weight
Hardness (Kp) 4.1 — 6.1
Thickness (mm) 3.85 — 3.96
Disintegration Time (sec) 58
Friability (%w/w) 0.07
[00147] Inference & Conclusion:
[00148] Physical parameters of Diclofenac Sublingual Tablets 50 mg were found satisfactory, but the taste and flavor were not satisfactory and further, the evaluation was done with wet granulation, as per the below changes and the composition and manufacturing process details as below.
[00149] Table 20: Unit Formula:

S. No. Ingredients Quantity per Unit
Batch No.: DSL-21-09
1 Diclofenac 50.00
2 Mannitol (Pearlitol SD 200) 150.00
3 Orange Flavour 9.00
4 Saccharine Sodium 6.00
5 Polacrilin Potassium (Amberlite IRP 88) 10.00
6 Crospovidone (Kollidon CL Cross Linked Polymer) 10.00
7 Aspartame (NutraSweet® Powder) 5.00
8 Microcrystalline Cellulose (Avicel PH-112) 25.00
9 Talc 6.00
10 Magnesium sterate 4.00
..
Tablet Weight 275.00

[00150] Table 21: Unit Formula:

S. No. Ingredients
_ Quantity per Unit
Intragranular Batch No.: DSL-21-09
1 Diclofenac
- 50
2 Mannitol (Pearlitol SD 200) 150
3 Orange Flavour 6.00
4 Saccharine Sodium 5.00
5 Purified Water q.s
_
Extragranular
6 Polacrilin Potassium (Amberlite IRP 88) 10.00
7 Crospovidone (Kollidon CL Cross Linked Polymer) 10.00
8 Aspartame (NutraSweet® Powder) 5.00
9 Saccharine Sodium
. 1.00
10 Orange Flavor 3.00
11 Microcrystalline Cellulose (Avicel PH-112) 25.00
12 Talc 6.00
13 Magnesium Sterate 4.00
Tablet Weight 275.00

[00151] 4.0) Brief manufacturing process
[00152] 4.1) Sifting:
[00153] 4.1.1) Sift together Diclofenac free acid through ASTM mesh no # 20
[00154] 4.1.2) Cosift Mannitol with Orange Flavor and Saccharine Sodium through 425pm sieve (ASTM mesh no #40).
[00155] 4.1.3) Cosift Step 4.1.1 with 4.1.2 through 4251im sieve (ASTM mesh no # 40). 4.1.4 Resift Step 4.1.3 through 425iim sieve (ASTM mesh no # 40).
[00156] 4.1.5) Loaded the sifted material of step 4.1.4 into a rapid mixer granulator and mixed for 10 minutes with impeller at slow speed and chopper in off position.
[00157] 4.1.6) Added the purified water (15% of dry mix) to the material of step 4.1.5 over a period of 1 minutes with impeller at slow speed and chopper in off position.
[00158] 4.1.7) Kneaded the wet mass of step 4.1.6 for 30 seconds or more with impeller at slow speed and chopper at slow speed.
[00159] 4.1.8) Unloaded the wet granular mass into the fluid bed dryer bowl with impeller at slow speed.
[00160] 4.1.9) Dry the wet mass of step 4.1.8 in the fluid bed dryer at an inlet air temperature of 55°C ± 10 °C to get LOD NMT 2.0% w/w.
[00161] 4.1.10) Sift the dried granules of step 4.1.9 through ASTM # 30 sieve. Mill the
retentions ensure all the granules should pass through ASTM # 30 sieve.
[00162] 4.1.11) Weigh extra granular as per the yield.
[00163] 4.1.12) Sift together polacrilin potassium, crospovidone, aspartame, saccharine sodium, orange flavor and microcrystalline cellulose through 425i.tm sieve (ASTM mesh no # 40).
[00164] 4.1.13) Load the granules of step 4.1.10 and sifted material of step 4.1.12 in to a low shear blender and blend for 30 minutes.
[00165] 4.1.14) If unloaded store the lubricated blend in suitable air tight container lined with double polythene bags kept in triple laminated aluminium bags followed by sealing. Further the blend was evaluated for the physical parameters of the tablets, the details as mentioned below:
[00166] Table 22: Compression Parameters:
Parameter Development Batch
Batch No.: DSL-21-09
Tooling 8.70 X 8.50 mm, Heart shaped, standard convex, embossed with ‘DF’ on upper punch and embossed with ‘50’ on lower punch.
Tablet description White to off-white, Heart shaped, biconvex, uncoated tablets debossed with ‘DF’ on one side and ‘50’ on other side.
Average weight (mg) 270 – 281
Uniformity of weight -2.1 to 1.5 % of target weight
Hardness (Kp) 4.1 – 6.3
Thickness (mm) 4.35 – 4.40
Disintegration Time (sec) 58 sec – 1 min 10 sec
Friability (%w/w) 0.08
[00167] Inference and Conclusion: Physical parameters of Diclofenac Sublingual Tablets 50 mg were found satisfactory, but the taste and flavor were not satisfactory, and further, the evaluation was done with direct mixing with two different flavors, as per the below changes and the composition and manufacturing process details as below.
[00168] The following Table 23 depicts Unit Formula:

S.No. Ingredients Quantity per Unit
Batch No.: DSL-21-20 Batch No.: DSL-21-21
1 Diclofenac free acid 46.560 46.560
2 Mannitol (Pearlitol SD 200) 123.440 123.440
3 Orange Flavor 15.000 -
4 Cherri Flavor - 15.000
5 Sodium starch glycolate (Type A) USNF (Primojel) 15.000 15.000
6 Croscarmellose sodium USNF 10.000 10.000
7 Microcrystalline Cellulose (Avicel PH-112) 15.000 15.000
8 Aspartame USNF (Aminosweet Power) 3.000 3.000
9 Colloidal silicon dioxide USNF (Aerosil) ® 200 Pharma 4.000 4.000
10 Sodium Stearyl Fumarate 8.000 8.000
Tablet Weight 240.00 240.000

[00169] 5.0) Brief manufacturing process
[00170] 5.1) Sifting
[00171] 5.1.1) Sift together Diclofenac free acid through 425 gm sieve (ASTM mesh no # 40). 5.1.2 Cosift Mannitol, Orange Flavor/ Art. Cherry flavor through 425 pm sieve (ASTM mesh no # 40)
[00172] 5.1.3) Cosift step 5.1.1 and step 5.1.2 through 425 gm sieve (ASTM mesh no # 40). 5.1.4 Cosift sodium starch glycolate and croscarmellose sodium through 425 gm sieve (ASTM mesh no # 40)
[00173] 5.1.5) Cosift microcrystalline cellulose, aspartame and colloidal silicon dioxide through 425 gm sieve (ASTM mesh no # 40).
[00174] 5.1.6) Sift sodium stearyl fumarate through 425 pm sieve (ASTM mesh no # 40).
[00175] 5.2) Mixing:
[00176] Load the material of step no 5.1.3 and step no 5.1.4 into suitable blender and blend for a period of 10 minutes.
[00177] 5.3) Pre-Lubrication
[00178] Add the material of step 5.1.5 to the blend of step 5.2 and blend for a period of 5 minutes.
[00179] 5.4) Lubrication: Load the sifted material of step 5.1.6 into the blend of step 5.3 and blend for a period of 5 minutes. If unloaded store the lubricated blend in suitable air tight container lined with double polythene bags kept in triple laminated Aluminium bags followed by sealing. Further the blend was evaluated for the physical parameters of the tablets, the details as mentioned below:
[00180] Table 24: Compression parameters:
Parameter Development Batch
Batch No.: DSL-21-20 Development Batch
Batch No.: DSL-21-21
Tooling 8.70 X 8.50 mm, Heart shaped, standard convex, embossed with `DF' on upper punch and embossed with '50' on lower punch.
Tablet description White to off-white, Heart shaped, biconvex,
uncoated tablets debossed with 'DF' on one side
and '50' on other side.
Average weight (mg) 238 — 242 239 — 246
Uniformity of weight -0.8 to 1.2 % of target
weight -0.5 to 2.5 % of target
weight
Hardness (Kp) 4.0 — 6.0 4.0 — 6.0
Thickness (mm) 4.80 — 4.83 4.80 — 4.85
Disintegration Time (sec) 37 sec 37 sec
Friability (%w/w) 0.09 0.09
[00181] Inference and Conclusion: Physical parameters of Diclofenac Sublingual Tablets 50 mg was found satisfactory with orange flavor/ Art. Cherry flavor. The taste and flavor was satisfactory and further the evaluation was done.
[00182] Based on the satisfactory physical parameter of tablet, the finished product was evaluated for the CQA's like dissolution profile.
[00183] Inference and Conclusion:
[00184] From the above dissolution data it can be inferred that dissolution profile of development batches of Diclofenac Sublingual Tablets 50 mg with Orange Flavor / Art. Cherry flavor meets the in-house dissolution specification that is NLT 75% Q in 10 minutes. Reproducible batch
[00185] Table 25: Unit Formula:

S. No. Ingredients Quantity per unit (mg)
B.No.DSL-21-22
1 Diclofenac free acid 46.560
2 Mannitol (Pearlitol SD 200) 123.440
3 Art. cherry flavor 15.000
4 Sodium starch glycolate (Type A) USNF
(Primojel) 15.000
5 Croscarmellose sodium USNF 10.000
6 Microcrystalline Cellulose (Avicel PH-112) 15.000
7 Aspartame USNF (Aminosweet Power) 3.000
8 Colloidal silicon dioxide USNF (Aerosil) 0 200 Pharma 4.000
9 Sodium Stearyl Fumarate 8.000
240.000

[00186] 6.0) Brief manufacturing process
[00187] 6.1) Sifting:
[00188] 6.1.1) Sift together Diclofenac free acid through 425 pm sieve (ASTM mesh no # 40).
[00189] 6.1.2) Cosift mannitol and Art.cherry flavor through 425 pm sieve (ASTM mesh no # 40)
[00190] 6.1.3) Cosift step 6.1.1 and step 6.1.2 through 425 pm sieve (ASTM mesh no # 40).
[00191] 6.1.4) Cosift sodium starch glycolate and croscarmellose sodium through through 425 pm sieve (ASTM mesh no # 40).
[00192] 6.1.5) Cosift microcrystalline cellulose, Aspartame and colloidal silicon dioxide through 425 pm sieve (ASTM mesh no # 40).
[00193] 6.1.6) Sift sodium stearyl furamate through 425 p.m sieve (ASTM mesh no # 40).
[00194] 6.2) Mixing:
[00195] Load the material of step no 6.1.3 and step no 6.1.4 into suitable blender and blend for a period of 10 minutes.
[00196] 6.3) Pre-Lubrication:
[00197] Add the material of step 6.1.5 to the blend of step 6.2 and blend for a period of 5 minutes.
[00198] 6.4) Lubrication:
[00199] Load the sifted material of step 6.1.6 into the blend of step 6.3 and blend for a period of 5 minutes.
[00200] If unloaded store the Lubricated blend in suitable air tight container lined with double polythene bags kept in triple laminated Aluminium bags followed by sealing. Further the blend was evaluated for the physical parameters of the tablets, the details as mentioned below;
[00201] Table 26: Compression Parameters:

Parameter Development Batch
Batch No.: DSL-21-22
_
Tooling 8.70 X 8.50 mm, Heart shaped, standard convex,
embossed with 'DF' on upper punch and embossed with '50' on lower punch.
Tablet description White to off-white, Heart shaped, biconvex,
uncoated tablets debossed with 'DF' on one side
and '50' on other side.
Average weight (mg) 238 — 247
Uniformity of weight 0.5 to 3.0 % of target weight
Hardness (Kp) 4.0 — 6.0
Thickness (mm) 4.80 — 4.83
Disintegration Time (sec) 37 sec
Friability (%w/w) 0.09

[00202] Inference and Conclusion:
[00203] Physical parameters of Diclofenac Sublingual Tablets 50 mg were found satisfactory with Art. Cherry flavor. The taste and flavor were satisfactory and further the evaluation was done.
[00204] Based on the satisfactory physical parameters of tablet, the finished product was evaluated for the CQA's like dissolution profile.
[00205] Inference and Conclusion:
[00206] From the above dissolution data it can be inferred that dissolution profile of development batches of Diclofenac Sublingual Tablets 50 mg with Art. Cherry flavor meets the dissolution in-house specification.
[00207] Based on the satisfactory dissolution data of tablets, the following compression parameters are finalized.
[00208] Table 27: Compression Parameters:

Parameter Development Batch
Batch No.: DSL-21-22
Tooling
(Tool drawing enclosed) 8.70 X 8.50 mm, Heart shaped, standard convex,
embossed with 'IN' on upper punch and embossed with '50' on lower punch.
Tablet description White to off-white, Heart shaped, biconvex,
uncoated tablets debossed with 'DF' on one side
and '50' on other side.
Average weight (mg) 240.00mg ± 2 %
Uniformity of weight ± 7.5 % of target weight
Hardness (Kp) 2.0 — 6.0
Thickness (mm) 4.80 ± 0.40
Disintegration Time (min) NMT 5
Friability (%w/w) NMT 1.0

[00209] Based on the satisfactory data of tablets, proceeded for evaluation of the finished product, details as captured in following sections.
[00210] The in-process parameters and finished product parameters were found satisfactory and meeting the specification limits. The in-process parameters and finished product parameters are summarized in the following tables.
[00211] Table 28: In-process parameters

Test (s) Acceptance Criteria Results
B. No.: SP-DSL-21-33
Description Whit to off white Powder
Water (% w/w, by KF) NMT 7 2.5
Assay (By HPLC)
Each 240 mg of blend
contains Diclofenac, in mg 45 — 55 49.5
% Labeled amount
(Mean Value) 90 - 110 98.9

[00212] Table 29: Finished Product Initial Evaluation of Diclofenac Sublingual Tablets 50 mg

Test (s) Acceptance Criteria Results
B. No.

DSL-21-32 DSL-21-33 DSL-21-34
Description White to pale yellow, Hart shaped, approximately 4 mm, tablets debossed with ‘DF’ on one side and ‘50’ on the other side. Complies Complies Complies
Identification
A) By UV – DAD The retention time and Spectra of the Diclofenac peaks in the chromatogram of the sample solution corresponds to that in the chromatogram of standard solution. Complies Complies Complies
B) By HPLC The retention time of the major peak in the chromatogram of the sample solution should correspond to that of the major peak in the chromatogram of the Standard solution, as obtained in the Assay. Complies Complies Complies
Average weight (mg) 228 - 252 246.0 245.0 245.7
Water by KF (% w/w) NMT 10 2.3 2.2 2.4
Assay
(By HPLC) % w/w
Each uncoated tablet contains Diclofenac Sodium, in mg 45 – 55 50.9 50.1 48.7
% Labeled amount 90 - 110 101.8 100.2 97.4
Dissolution
(By HPLC) NLT 75 Q in 10 minutes 97 95 96
Uniformity of Dosage units (By content uniformity) Acceptance value (AV) NMT 15 12.1 14.7 13.6
Related Substances (By HPLC)
Impurity - A NMT 0.2 ND ND ND
Impurity - F NMT 0.2 ND ND ND
Any unspecified degradation product NMT 0.2 BDL BDL BDL
Total degradation products NMT 1.0 ND ND ND

[00213] 7.0) Updated risk assessment on drug product CQA
[00214] Based on the results of the development batch and exhibit batch, the initial risk assessment on drug product CQA was updated as given in the table below.
[00215] Table 30: Updated risk assessment

Drug Product CQA Level of risk Rationale
Dissolution Low The dissolution of Diclofenac sublingual tablets 50 mg was evaluated and meets specifications. Hence the risk is reduced from medium to low.

[00216] 8.0) Container Closure System
[00217] The choice of the container closure system is based on the acceptable accelerated stability data of the laboratory scale batches. The same container closure system is proposed.
[00218] The following container and closure system are proposed for commercial packing. Table 31:

Product Name Market Pack Type
Diclofenac Sublingual Tablets 50 mg In-House 15’s count clear PVC – plain paper backed push through lidding blister 25µ

[00219] 9.0) Control Strategy
[00220] The control strategy for the commercial manufacturing of generic Diclofenac Sublingual Tablets 50 mg is proposed and presented in table below. This includes control strategy for raw material attributes and control strategy for Drug product to be controlled and proposed operating ranges for commercial batches.
[00221] Table 32: Control Strategy for Drug product

Factor Attributes or Parameters Range Finalized Actual data for exhibit batch Proposed range for commercial scale Purpose of Control
Blending
(in minutes) Pre-blending 10 – 30 10 10 To ensure batch to batch consistency
Pre-lubrication
Time (mm) 5 5 5
Lubrication
Time (mm) 5 5 5
Compression Tooling 8.70 X 8.50 mm, Heart shaped, standard convex, embossed with ‘DF’ on upper punch and embossed with ‘50’ on lower punch 8.70 X 8.50 mm, Heart shaped, standard convex, embossed with ‘DF’ on upper punch and embossed with ‘50’ on lower punch 8.70 X 8.50 mm, Heart shaped, standard convex, embossed with ‘DF’ on upper punch and embossed with ‘50’ on lower punch
Tablet description White to off-white, Heart shaped, biconvex, uncoated tablets debossed with ‘DF’ on one side and ‘50’ on other side. White to off-white, Heart shaped, biconvex, uncoated tablets debossed with ‘DF’ on one side and ‘50’ on other side. White to off-white, Heart shaped, biconvex, uncoated tablets debossed with ‘DF’ on one side and ‘50’ on other side.
Average weight (mg) 240 mg ± 3.0% 240 mg ± 3.0% 240 mg ± 3.0%

Uniformity of weight 5.0 % of target weight 5.0 % of target weight 5.0 % of target weight
Hardness
(Kp) 2.5 - 8 2.5 - 8 2.5 - 8
Thickness
(mm) 4.40 ± 0.40mm 4.40 ± 0.40mm 4.40 ± 0.40mm
Disintegration
Time (min) NMT 5 NMT 5 NMT 5
Friability
(% w/w) NMT 1.0 NMT 1.0 NMT 1.0

[00222] 10.0) Stability Studies:
[00223] Table 33: Stability Evaluation of Diclofenac Sublingual Tablets 50 mg

Test (s) Acceptance Criteria Results
Condition: 40 °C/ 75% RH – 1 Months
DSL-21-32 DSL-21-33 DSL-21-34
Description White to pale yellow, Hart shaped, approximately
4 mm, tablets debossed with ‘DF’ on one side and ‘50’ on the other side. Complies Complies Complies
Identification
A) By UV – DAD The retention time and Spectra of the Diclofenac peaks in the chromatogram of the sample solution corresponds to that in the chromatogram of standard solution. Complies Complies Complies
B) By HPLC The retention time of the major peak in the chromatogram of the sample solution should correspond to that of the major peak in the chromatogram of the Standard solution, as obtained in the Assay. Complies Complies Complies
Average weight (mg) 228 - 252 242.9 248.8 242.8
Water by KF
(% w/w) NMT 10 2.61 2.92 2.34
Assay (By HPLC) % w/w
Each uncoated tablet contains Diclofenac Sodium, in mg 45 – 55 50 51.7 48.8
% Labeled amount 90 - 110 99.9 103.3 97.6
Dissolution (By HPLC) NLT 75 Q in 10 minutes 101 86 93
Related Substances (By HPLC)
Impurity - A NMT 0.2 0.01 BDL BDL
Impurity - F NMT 0.2 0.01 0.01 0.01
Any unspecified degradation product NMT 0.2 BDL BDL BDL
Total degradation products NMT 1.0 0.02 0.01 0.01

[00224] Table 34: Stability Evaluation of Diclofenac Sublingual Tablets 50 mg

Test (s) Acceptance Criteria Results
Condition: 40 °C/ 75% RH – 3 Months
DSL-21-32 DSL-21-33 DSL-21-34
Description White to pale yellow, Hart shaped, approximately 4 mm, tablets debossed with ‘DF’ on one side and ‘50’ on the other side. Complies Complies Complies
Identification
A. By UV – PDA The retention time and Spectra of the Diclofenac peaks in the chromatogram of the sample solution corresponds to that in the chromatogram of standard solution. Complies Complies Complies
B. By HPLC The retention time of the major peak in the chromatogram of the sample solution should correspond to that of the major peak in the chromatogram of the Standard solution, as obtained in the Assay. Complies Complies Complies
Average weight (mg) 228 - 252 241.2 242.8 242.1
Water by KF (% w/w) NMT 10 2.80 2.90 2.82
Assay (By HPLC) % w/w
Each uncoated tablet contains Diclofenac, in mg 45 – 55 49.8 49.7 50.1
% Labeled amount 90 - 110 99.6 99.4 100.1
Dissolution (By HPLC) NLT 75 Q in 10 minutes 95 93 96
Related Substances (By HPLC)
Impurity - A NMT 0.2 ND ND ND
Impurity - F NMT 0.2 0.01 0.01 0.01
Any unspecified degradation product NMT 0.2 0.05 0.07 0.07
Total degradation products NMT 1.0 0.06 0.08 0.08

[00225] Table 35: Stability Evaluation of Diclofenac Sublingual Tablets 50 mg

Test (s) Acceptance Criteria Results
Condition: 40 °C/ 75% RH – 6 Months
DSL-21-32 DSL-21-33 DSL-21-34
Description White to pale yellow, Hart shaped, approximately 4 mm, tablets debossed with ‘DF’ on one side and ‘50’ on the other side. Complies Complies Complies
Identification
A. By UV – PDA The retention time and Spectra of the Diclofenac peaks in the chromatogram of the sample solution corresponds to that in the chromatogram of standard solution. Complies Complies Complies
B. By HPLC The retention time of the major peak in the chromatogram of the sample solution should correspond to that of the major peak in the chromatogram of the Standard solution, as obtained in the Assay. Complies Complies Complies
Average weight (mg) 228 - 252 247.3 247.0 247.1
Water by KF (% w/w) NMT 10 3.7 2.5 1.6
Assay (By HPLC) % w/w
Each uncoated tablet contains Diclofenac, in mg 45 – 55 50.0 51.2 49.7
% Labeled amount 90 - 110 99.9 102.3 99.3
Dissolution (By HPLC) NLT 75 Q in 10 minutes 91 83 83
Related Substances (By HPLC)
Impurity - A NMT 0.2 0.01 0.01 ND
Impurity - F NMT 0.2 0.01 0.01 0.01
Any unspecified degradation product NMT 0.2 0.04 0.05 0.05
Total degradation products NMT 1.0 0.06 0.07 0.06

[00226] Table 36: Drug Product Specification for Diclofenac Sublingual Tablets 50 mg

Test (s) Release Specification Shelf-Life Specification
Description White to pale yellow, Hart shaped, approximately 4 mm, tablets debossed with ‘DF’ on one side and ‘50’ on the other side. White to pale yellow, Hart shaped, approximately 4 mm, tablets debossed with ‘DF’ on one side and ‘50’ on the other side.
Identification
A. By UV – DAD The retention time and Spectra of the Diclofenac peaks in the chromatogram of the sample solution corresponds to that in the chromatogram of standard solution. The retention time and Spectra of the Diclofenac peaks in the chromatogram of the sample solution corresponds to that in the chromatogram of standard solution.
B. By HPLC The retention time of the major peak in the chromatogram of the sample solution should correspond to that of the major peak in the chromatogram of the Standard solution, as obtained in the Assay. The retention time of the major peak in the chromatogram of the sample solution should correspond to that of the major peak in the chromatogram of the Standard solution, as obtained in the Assay.
Average weight (mg) 228 - 252 228 - 252
Water by KF (% w/w) NMT 7 NMT 10
Assay (By HPLC) % w/w
Each uncoated tablet contains Diclofenac, in mg 45 – 55 45 – 55
% Labeled amount 90 - 110 90 - 110
Dissolution (By HPLC) NLT 75 Q in 10 minutes NLT 75 Q in 10 minutes
Related Substances (By HPLC)
Impurity - A NMT 0.2 NMT 0.2
Impurity - F NMT 0.2 NMT 0.2
Any unspecified degradation product NMT 0.2 NMT 0.2
Total degradation products NMT 0.7 NMT 1.0

[00227] Diclofenac Sublingual Tablets 50 mg was developed as an immediate release (IR) dosage form and is indicated for treatment of primary dysmenorrhea, for relief of mild to moderate pain, for relief of the signs and symptoms of osteoarthritis, for relief of mild to moderate pain, for relief of the signs and symptoms of osteoarthritis, for relief of the signs and symptoms of rheumatoid arthritis, for relief of symptoms of ankylosing spondylitis and for relief of acute migraine symptoms. For Diclofenac Sublingual Tablets 50 mg, a direct mixing and blending process is selected based on prior experience and formulation requirements. Development batch of Diclofenac Sublingual Tablets 50 mg was found satisfactory for all critical quality attributes (CQA's) against the approved specification. Dissolution profile was meeting the approved in-house specification limit of NLT 75% Q in 10 min. The drug release from dosage form was rapid as more than 80% of the drug was released at 10 minutes time point.
[00228] They act like oral solutions for immediate-release products with faster dissolution, hence the dissolution profile is unlikely to have impact on the pharmacokinetic parameters and bioavailability of drug product.
[00229] Risk assessment approaches were applied throughout development of drug product to identify potential risk in formulation and process variations and also to determine what studies were necessary to achieve product quality. By understanding the risk assessment, a control strategy is developed.
[00230] Based on the process development and understanding of CQAs, the identified risk assessments have been updated to reduce the level of risk in Diclofenac Sublingual Tablets 50 mg.
[00231] Finally, we proposed a control strategy; it includes the critical process parameters that were identified as potentially risk variables during the initial risk assessments.
[00232] Control strategy is also applied for in-process controls of manufacturing process and finished product specifications. The process will be monitored during the lifecycle of the product and additional knowledge gained will be utilized to make adjustments to the control strategy as appropriate.
[00233] A person skilled in the art will understand that the solid pharmaceutical sublingual oral dosage composition is described herein for illustrative purposes and should not be construed to limit the scope of the disclosure.
[00234] A person with ordinary skills in the art will appreciate that the method and composition have been illustrated and explained to serve as examples and should not be considered limiting in any manner. It will be further appreciated that the variants of the above-disclosed system elements, modules, and other features and functions, or alternatives thereof, may be combined to create other different apparatuses, systems, or applications.
[00235] While the present disclosure has been described with reference to certain embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the present disclosure without departing from its scope. Therefore, it is intended that the present disclosure not be limited to the particular embodiment disclosed, but that the present disclosure will include all embodiments falling within the scope of the appended claims.
,CLAIMS:CLAIMS

I/We claim:
1. A method for obtaining a solid pharmaceutical sublingual oral dosage composition containing a diclofenac-free acid, comprising:

dispensing a plurality of first input materials comprising diclofenac free acid, mannitol, and artificial cherry flavor, wherein the dispensed diclofenac free acid, mannitol and artificial cherry flavor are sieved through an appropriate size screen mesh;

sieving a plurality of second input materials comprising sodium starch glycolate and croscarmellose sodium through the appropriate size screen mesh;

blending the first input materials and the second input materials to obtain a first uniform blend;

dispensing a plurality of third input materials comprising microcrystalline cellulose, aspartame, and colloidal silicon dioxide, wherein the microcrystalline cellulose, aspartame, and colloidal silicon dioxide are sieved through the appropriate size screen mesh;

blending the third input materials with the first uniform blend to obtain a second uniform blend;

dispensing a fourth input material comprising sodium stearyl fumarate, wherein the sodium stearyl fumarate is sieved through the appropriate size screen mesh;

blending the fourth input material with the second uniform blend to obtain a final uniform blend, wherein the final uniform blend comprises the solid pharmaceutical sublingual oral dosage composition containing the diclofenac-free acid.
2. The method as claimed in claim 1 comprises a step of compressing the solid pharmaceutical sublingual oral dosage composition to obtain a plurality of tablets.
3. The method as claimed in claim 1 comprises a step of performing an in-process sampling to provide one or more of a content uniformity, weight variation hardness, and weight variation thickness.
4. The method as claimed in claim 1 comprises a step of packaging the tablets which is delivered through the sublingual route.
5. The method as claimed in claim 2, wherein the solid pharmaceutical sublingual oral dosage composition is compressed by a Rotary Tablet Press.
6. The method as claimed in claim 1, wherein the appropriate size screen mesh has a sieve dimension of 425 pm.
7. The method as claimed in claim 1, wherein the solid pharmaceutical sublingual oral dosage composition has an average weight (mg) of about 235 mg to 245 mg.
8. The method as claimed in claim 1, wherein the solid pharmaceutical sublingual oral dosage composition comprising 46.560 mg of diclofenac free acid, 123.440 mg of mannitol, 15.000 mg of artificial cherry flavor, 15.000 mg of sodium starch glycolate, 10.000 mg of croscarmellose sodium, 15.000 mg of microcrystalline cellulose, 3.000 mg of aspartame, 4.000 mg of colloidal silicon dioxide, and 8.000 mg of sodium stearyl fumarate.
Dated November 11, 2022
Chaitanya Rajendra Zanpure
Agent for the Applicant
IN-PA-2282