DESC:TECHNICAL FIELD
The present disclosure relates to the field of pharmaceutical composition. More particularly, the present disclosure relates to Levothyroxine Sodium pellets and capsules composition and method of preparation.
BACKGROUND
Levothyroxine treats hypothyroidism in adults and children by replacing thyroxine, a hormone essential for metabolism. It is also used with surgery and radioactive iodine for certain thyroid cancers and, in injection form, for myxoedema coma. Levothyroxine Sodium pellets has encountered several challenges and limitations that necessitate ongoing research and development efforts. These issues revolve around the formulation, coating, and preparation processes, posing hurdles to achieving optimal bioavailability, stability, and therapeutic efficacy.
Currently available formulations of levothyroxine sodium pellets have exhibited inconsistent dissolution profiles. Levothyroxine (L-T4) has a narrow therapeutic index, making small dosage changes potentially harmful, leading to therapeutic failure or adverse events. Despite the availability of bioequivalent brands and generics, patients often experience loss of therapeutic control after switching products. This variability is partly due to L-T4’s sensitivity to stability and potency issues. In some cases, therapeutic efficacy improved when tablets were pulverized, likely due to slow dissolution rates. Classified as a Class III drug (high solubility, low permeability), L-T4's absorption is highly variable. Its solubility is nearly 100% at acidic pH levels (1.2 and 2.4) but drops below 60% at pH 4.0 and less than 40% at pH 5.0, explaining inconsistent absorption across different formulations.
Achieving a reliable and reproducible release of the active ingredient in media solutions with pH levels between 5 and 5.5 has been a persistent challenge. This lack of consistency raises concerns about the reliability of drug delivery and the potential impact on therapeutic outcomes.
Modified-release formulations could enhance therapeutic consistency by optimizing dissolution at relevant pH levels. Modified-release (MR) drug delivery systems control the rate and site of drug release, offering enhanced efficacy, reduced side effects, and improved patient compliance compared to conventional forms. An emerging example is the Modified Release Levothyroxine Sodium Capsules, addressing key limitations of traditional tablets. Unlike the current Levothyroxine tablets, which must be taken on an empty stomach to ensure proper absorption, the modified release capsules are designed to release the drug at pH 5.5. This allows them to be taken at any time of day, regardless of food intake, enhancing patient convenience and adherence. These capsules feature a protective coating that shields the drug from stomach acid, ensuring it reaches the intestine for optimal absorption. Further, being a synthetic hormone, Levothyroxine Sodium modified-release capsules restore proper hormone levels, alleviating symptoms like tiredness, weight gain, and muscle aches. Most patients require lifelong treatment, and discontinuation should only occur under medical supervision.
In many of the commercially available compositions, the variation in quantities of key components, such as levothyroxine sodium, sodium citrate, starch, lactose anhydrous, and acacia powder, has led to inconsistent performance across different batches. The lack of standardized composition parameters has resulted in difficulties in ensuring uniform drug content and properties among the pellets.
EP2885005 discloses a pharmaceutical composition of a solid pharmaceutical preparation comprising levothyroxine sodium, gelatine, citric acid and a filler where the filler in the solid preparation of the present invention is preferably a sugar alcohol, a sugar, a starch, a cellulose or a mixture thereof. Further includes an antioxidant selected from the group consisting of tocopherol, sodium ascorbate, propyl gallate, tertiary butylhydroquinone, butylated hydroxyanisole and butylated hydroxytoluene (BHT), preferably butylated hydroxyanisole or butylated hydroxytoluene, particular preferably butylated hydroxytoluene, where the antioxidant is dissolved in in the aqueous gelatine solution or is admixed with the granules.
US2014178511 discloses a pharmaceutical composition comprising thyroxine, acacia, and an antioxidant selected from propyl gallate, butylated hydroxyanisol, and butylated hydroxytoluene is where the pharmaceutical composition has an improved shelf life. The composition additionally comprises sucrose, microcrystalline cellulose, and mannitol. The pharmaceutical composition is used for treating thyroid disorders by orally administering the composition to a patient in need thereof.
EP4061331 provides oral film dosage forms that are formulated or administered for gastrointestinal absorption of the active pharmaceutical agent. These oral films are mouth dissolving or soluble film, non-mucoadhesive film, fast disintegrating film; they quickly disintegrate in the mouth when exposed to saliva; and they are absorbed predominantly through the gastrointestinal tract. Further, each oral film comprises - (i) levothyroxine or its salt, (ii) a film forming polymer, and (iii) a plasticizer.
IN3703/MUM/2014 discloses storage stable oral pharmaceutical compositions of a thyroid hormone drug or pharmaceutically acceptable salts thereof and methods by which they are produced. The methods involve a granulation step comprising a thyroid hormone drug and one or more saccharides to provide a formulation having better stability of both the granulation intermediates and the final oral dosage forms prepared from these granulation intermediates.
Therefore, the preferred object of the invention is directed to a solid pharmaceutical preparation, which is characterized in that it further comprises an antioxidant selected from the group consisting of tocopherol, propyl gallate, tertiary butylhydroquinone, butylated hydroxyanisole and butylated hydroxytoluene, preferably hydroxyanisole or butylated hydroxytoluene, particular preferably butylated hydroxytoluene.
Prior art methods have faced difficulties in achieving uniform-sized pellets suitable for encapsulation. The sieving process, intended to obtain pellets within the range of 1.00 mm to 0.710 mm, has been prone to inefficiencies, leading to a lack of control over the final product's physical characteristics.
Therefore, there is a need for a solution to overcome the aforementioned problems associated with the prior arts. The innovative formulation of the present invention overcomes challenges associated with conventional Levothyroxine tablets, offering a more effective and user-friendly treatment option.

SUMMARY
In one aspect of the present disclosure, a composition for Levothyroxine Sodium pellets is provided. The composition includes sugar pellets ranging from 1500 to 8500 grams of the composition. The composition further includes levothyroxine sodium ranging from 2 to 10 grams of the composition. The composition includes sodium citrate ranging from 80-350 grams of the composition. The composition includes sodium lauryl sulphate ranging from 120-240 grams of the composition. The composition includes starch ranging from 600-2200 grams of the composition. The composition includes lactose anhydrous ranging from 600- 3000 grams of the composition. The composition includes acacia powder ranging from 50-350 grams of the composition. The composition is film-coated to pellet, in the range of 270 mg to 320 mg to enclose in a capsule.
In some aspects of the present invention disclosure, the composition further includes a film coating solution that are selected from methacrylate polymer and a surfactant dissolved in a solvent.
In some aspects of the present invention disclosure, the film-coated pellets are subjected to dissolution between pH 5 and 5.5 media solution in a USP type 2 dissolution apparatus.
In some aspects of the present invention disclosure, levothyroxine pellets and filler neutral pellets forms 100mcg/capsule.
In some aspects of the present invention disclosure, the uniformly sized pellets ranges from 1.00 mm to 0.710 mm size.
In some aspects of the present invention disclosure, uniformity of fill weight of the pellet is at a variation of 7.5%.
In some aspects of the present invention disclosure, where the capsule material is selected from gelatin, collagen or hydroxy propyl methyl cellulose.
In second aspect of the present disclosure, a method for preparing levothyroxine sodium pellets for use in capsules is provided. The method includes combining sugar pellets, levothyroxine sodium, sodium citrate, starch, lactose anhydrous, and acacia powder. The method further includes mixing levothyroxine sodium, sodium citrate, starch, lactose anhydrous, acacia powder and sodium lauryl sulphate in a geometric progression to create a homogenous coating powder. The method further includes loading sugar pellets onto a coating pan of specific mesh size. The method further includes setting the coating pan to revolve at 10-100 RPM. The method further includes spraying a measured volume of binding solution onto sugar pellets intermittently. The method further includes coating the pellets with the coating powder until exhausted. The method further includes unloading and drying the coated pellets at 45 to 55 degrees Celsius for 8-16 hours. The method further includes sieving to obtain uniform-sized pellets of 1.00 mm to 0.710 mm.
BRIEF DESCRIPTION OF DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, show certain aspects of the subject matter disclosed herein and, together with the description, help explain some of the principles associated with the disclosed implementations. In the drawing,
Figure 1 illustrates a flowchart that depicts a method of preparation of levothyroxine sodium pellets, in accordance with an aspect of the present disclosure.
Figure 2 illustrates a graphical representation of the acid dissolution of levothyroxine standard at a pH of 3.5, in accordance with an aspect of the present disclosure.
Figure 3 illustrates a graphical representation of the acid dissolution of levothyroxine capsule at a pH of 3.5, in accordance with an aspect of the present disclosure.
Figure 4 illustrates a graphical representation of the buffer dissolution of levothyroxine standard at a pH of 5.5, in accordance with an aspect of the present disclosure.
Figure 5 illustrates a graphical representation of the buffer dissolution of levothyroxine capsule at a pH of 5.5, in accordance with an aspect of the present disclosure.
Figure 6 illustrates a graphical representation of dissolution assay of Levothyroxine standard, in accordance with an aspect of the present disclosure.
Figure 7 illustrates Levothyroxine capsule dissolution assay for the sample trials, in accordance with an aspect of the present disclosure.
Figure 8 illustrates a graphical representation representing the uniformity of contents in terms of levothyroxine standard.
Figure 9 illustrates a graphical representation representing the uniformity of contents in terms of Levothyroxine capsule.
Figure 10 the uniformity in terms of Levothyroxine bracketing standard, in accordance with an aspect of the present disclosure.
Figure 11 illustrates a graphical representation of comparative evaluation of dissolution and assay between Liothyronine and Levothyroxine
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Various embodiments of the disclosure are discussed in detail below. While specific implementations are discussed, it should be understood that this is done for illustration purposes only. A person skilled in the relevant art will recognize that other components and configurations may be used without parting from the spirit and scope of the disclosure. Thus, the following description and drawings are illustrative and are not to be construed as limiting. Numerous specific details are described to provide a thorough understanding of the disclosure. However, in certain instances, known details are not described in order to avoid obscuring the description.
References to one or an embodiment in the present disclosure can be references to the same embodiment or any embodiment; and such references mean at least one of the embodiments.
Reference to "one embodiment", "an embodiment", “one aspect”, “some aspects”, “an aspect” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments. Moreover, various features are described which may be exhibited by some embodiments and not by others.
The terms used in this specification generally have their ordinary meanings in the art, within the context of the disclosure, and in the specific context where each term is used. Alternative language and synonyms may be used for any one or more of the terms discussed herein, and no special significance should be placed upon whether or not a term is elaborated or discussed herein. In some cases, synonyms for certain terms are provided.
A recital of one or more synonyms does not exclude the use of other synonyms.
The use of examples anywhere in this specification, including examples of any terms discussed herein, is illustrative only and is not intended to further limit the scope and meaning of the disclosure or of any example term. Likewise, the disclosure is not limited to various embodiments given in this specification. Without intent to limit the scope of the disclosure, examples of instruments, apparatus, methods and their related results according to the embodiments of the present disclosure are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the disclosure. Unless otherwise defined, technical and scientific terms used herein have the meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the case of conflict, the present document, including definitions, will control.
Additional features and advantages of the disclosure will be set forth in the description which follows, and in part will be obvious from the description, or can be learned by practice of the herein disclosed principles. The features and advantages of the disclosure can be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These and other features of the disclosure will become more fully apparent from the following description and appended claims or can be learned by the practice of the principles set forth herein.
As mentioned before, there is a need for technology that overcomes these drawbacks associated with the prior arts. The present disclosure therefore provides a Levothyroxine Sodium pellets composition and method of preparation of the Levothyroxine Sodium pellets and capsules.
In one aspect of the present disclosure, a composition for Levothyroxine Sodium pellets is provided. The composition includes sugar pellets ranging from 1500 to 8500 grams of the composition. The composition further includes levothyroxine sodium ranging from 2 to 10 grams of the composition. The composition includes sodium citrate ranging from 80-350 grams of the composition. The composition further includes sodium lauryl sulphate ranging from 120-240 grams of the composition. The composition includes starch ranging from 600-2200 grams of the composition. The composition includes lactose anhydrous ranging from 600-3000 grams of the composition. The composition includes sugar ranging from 1000 gms to 2000 gms of the composition. The composition includes acacia powder ranging from 50-350 grams of the composition.
In some aspects of the present disclosure, the composition further includes a film coating solution that are selected from methacrylate polymer and a surfactant dissolved in a solvent.
In some aspects of the present disclosure, the film-coated pellets are subjected to dissolution between pH 5 and 5.5 media solution in a USP type 2 dissolution apparatus.
In some aspects of the present disclosure, the levothyroxine sodium may be present in an amount ranging from 4 to 6 grams.
In some aspects of the present disclosure, the sodium citrate may be present in an amount ranging from 90 to 110 grams.
In some aspects of the present disclosure, the starch may be present in an amount ranging from 800 to 1000 grams.
In some aspects of the present disclosure, the lactose anhydrous may be present in an amount ranging from 800 to 1000 grams.
In some aspects of the present disclosure, sodium lauryl sulphate ranging from 120-240 grams of the composition
In some aspects of the present disclosure, the acacia powder is present in an amount ranging from 80 to 120 grams.
In some aspects of the present disclosure, the composition is film coated to a pellet, in the range of 270 mg to 320 mg to enclose in a capsule.
In some aspects of the present invention disclosure, includes a film coating solution that are selected from methacrylate polymer and a surfactant dissolved in a solvent.
In some aspects of the present invention disclosure, the film-coated pellets are subjected to dissolution between pH 5 and 5.5 media solution in a USP type 2 dissolution apparatus. The preferred pH range of product overcomes the requirement of taking the dose on empty stomach.
In some aspects of the present invention disclosure, the levothyroxine pellets and filler neutral pellets forms 100mcg/capsule.
In some aspects of the present invention disclosure, the uniformly sized pellets ranges from 1.00 mm to 0.600 mm size.
In some aspects of the present invention disclosure, the uniformity of fill weight of the pellet is at a variation of 7.5%.
In some aspects of the present invention disclosure, the capsule material is selected from gelatin, collagen or hydroxypropyl methyl cellulose.
Figure 1 illustrates a flowchart that depicts a method of preparation of levothyroxine sodium pellets, in accordance with an aspect of the present disclosure. The method 100 may include the following steps:
At step 102, the method 100 may include combining sugar pellets, levothyroxine sodium, sodium citrate, sodium lauryl sulphate, starch, lactose anhydrous, and acacia powder.
At step 104, the method 100 may include mixing levothyroxine sodium, sodium citrate, sodium lauryl sulphate, starch, lactose anhydrous, acacia powder in a geometric progression to create a homogenous coating powder.
At step 106, the method 100 may include loading sugar pellets onto a coating pan of specific mesh size.
At step 108, the method 100 may include setting the coating pan to revolve at 10-100 RPM.
At step 110, the method 100 may include spraying a measured volume of binding solution onto sugar pellets intermittently.
At step 112, the method 100 may include coating the pellets with the coating powder until exhausted.
At step 114, the method 100 may include unloading and drying the coated pellets at 45 to 55 degrees Celsius for 8-16 hours.
At step 116, the method 100 may include sieving to obtain uniform-sized pellets of 1.00 mm to 0.710 mm.
In some aspects of the present invention disclosure, the mesh size of the sugar pellets for loading to the coating pan is 24/30 BSS especially ranging from 0.600 mm to 0.500 mm.
In some aspects of the present invention disclosure, the pellets undergoes sieve test and analyzed for uniformity of drug content, loss on drying, bulk density and dissolution at pH 5-5. 5 media solution, viz. Loss on drying 0.66% Bulk density 0.836.
In some aspects of the invention the dissolution testing involved selecting a suitable dissolution medium based on the solubility of the drug where the solution state stability is taken at a physiologic pH range 3.5 and 5.5. The selection of appropriate conditions for routine testing includes discriminatory dissolution, stability of analyte and relevance to in vitro performance.
In an exemplary scenario of the present invention disclosure, a composition for Levothyroxine Sodium IP pellets were prepared. The composition comprises sugar pellets ranging from 1500 to 5000 grams of the composition; levothyroxine sodium ranging from 2 to 8 grams of the composition; sodium citrate ranging from 80-120 grams of the composition; starch ranging from 600-1200 grams of the composition;
lactose anhydrous ranging from 600- 1200 grams of the composition; sodium lauryl sulphate ranging from 120-240 grams of the composition; and acacia powder ranging from 50-150 grams of the composition; wherein composition is film coated to pellet, in the range of 270 mg to 320 mg to enclose in a capsule. The pellets are processed to obtain drug content within a range so that the end product (pellets filled into capsules) of Levothyroxine Sodium IP of various strengths ranging from 2.5 mcg to 200 mcg.
In an exemplary scenario, the composition includes 10 gms of levothyroxine 200 gms of sodium citrate, further includes starch 1620 gms, lactose anhydrous 1800 gms, sodium lauryl sulphate ranging from 240 grams, acacia powder 200 grams of the composition.
In an exemplary scenario, the batch size were in the range of 9.00 kgs or multiples thereof , further for per 9.00 kg batch size 10 gms of Levothyroxine Sodium were coated. As the batch size increases or decreases the quantity of Levothyroxine Sodium coated will increase or decrease proportionately. The composition of the levothyroxine pellets of a batch of 5.5 kgs includes Sugar pellets 2500 gms, levothyroxine Sodium IP 5.0 gms, Sodium Citrate IP 100 gms, Starch IP 810 gms, Lactose Anhydrous IP 900 gms., Acacia Powder 100 gms, Sodium Lauryl Sulphate 90 gms, Pharmagrade sugar 1000 gms or multiples thereof. All the materials as indicated are analysed as per the relevant pharmacopoeia (Indian Pharmacopoeia or US Pharmacopoeia or British Pharmacoepia). The materials namely levothyroxine Sodium IP 5.5 gms, Sodium Citrate IP 100 gms, Starch IP 810 gms, Lactose Anhydrous IP 900 gms., Acacia Powder 100gms, Sodium Lauryl Sulphate 90 gms are mixed in a geometric progression to obtain a homogenous powder now labelled as coating powder. The coating powder is coated on the sugar pellets by a layering process wherein the binding solution (sugar dissolved in purified water) is sprayed on the sugar pellets.
In an exemplary scenario of the present invention disclosure, a method (100) for preparing Levothyroxine Sodium IP pellets to enclose in a capsule is provided. The sugar pellets of a specific mesh size were loaded onto a coating pan of size 24/30 BSS(0.600 mm to 0.500). The stainless steel coating pan was set to revolve at 18 rpm during the process The binding solution (sugar dissolved in purified water) of a measured volume was sprayed onto the sugar pellets in the pan through a spraying system with a peristaltic pump and a fan jet nozzle. The coating powder in a measured weight is coated/applied onto the sugar pellets and the pellets were allowed to roll and the process of spraying the binding solution followed by coating or specifically layering of the coating powder was done intermittently till the powder is exhausted. The pellets were unloaded into stainless trays and dried at 45 degrees to 55 degrees in a tray drier for 12 hours. The resultant dried pellets were sieved to obtain a uniform size of pellets of 1.00 mm to 0.710 mm size (BSS mesh size 16 to 22) The pellets are uniform in size and spherical in shape. The pellets undergo a sieve test and analysed.
In an exemplary scenario, the levothyroxine pellets and filler neutral pellets forms 100mcg/capsule. The pellets containing Levothyroxine Na 137 mg in a capsules and neutral pellets (without active ingredient Levothyroxine Sodium) containing only excipients 158 mg.
In an exemplary scenario of the present invention disclosure, the pellets on approval for sieve size, shape, uniformity of drug content and loss on drying were further film coated in the coating pan with a film coating solution having methacrylate polymer and a surfactant dissolved in a solvent in a pre-calculated quantity. 160 to 200 gms of methyl acrylate in 9.01 kg batch size and surfactant 16 gms to 20 gms of Tween 80 were used . Further, Methyl acrylate and Tween 80 dissolved in 3520 gms to 4400 gms of Isopropanol.The coating solution was sprayed/applied onto the Levothyroxine pellets through a spraying system with a specific hollow cone nozzle. On completion the pellets were unloaded into stainless trays and dried in a tray drier at 45 degrees Centigrade to 55 degrees centigrade. The resultant dried pellets were sieved to obtain a uniform size of pellets of 1.00 mm to 0.710 mm size. The pellets were uniform in size and spherical in shape.
The pellets undergo a sieve test and are analysed for uniformity of drug content, loss on drying, bulk density and dissolution at pH 5 media solution. The dissolution of levothyroxine sodium may take place between 5 pH and 5.5 pH media solution of 500 ml in a USP type 2 dissolution apparatus.
The approved pellets of one or more ware blended and filled into capsules and capsules were analysed. The capsules also undergo the dissolution between 5 pH and 5.5 pH media solution of 500 ml in a USP type 2 dissolution apparatus.
The product was developed based on dissolution required at two different pHs - 3.5 and 5.5.
At pH 3.5, no release is identified, since the pellets are film coated as desired .
At pH 5.5 release takes places at jejunum or ileum of the small intestine as the small intestine is proposed to be the predominant site for LT4 absorption. The two separate conditions are based on the product development which is to overcome the requirement of taking the dose on empty stomach; upon said basis of a range was selected .

Product Specification:
In an exemplary scenario of the present invention disclosure, the Levothryroxine Sodium Capsules of the present invention disclosure appear in the form of size ‘2’ capsules with pink opaque cap or any other colour and clear transparent body containing a mixture of white coloured off white coloured and spherical pellet and a shelf-life of 2 years from the date of manufacturing. The capsule has a fill weight of 295 mg, with a uniformity of ± 7.5 %. Each hard gelatine capsule contains Levothyroxine Sodium I.P - 100 mcg.
An exemplary scenario of the product specification -Levothryroxine Sodium Capsules is provided. The Levothyroxine Sodium Capsules were designed to meet stringent pharmaceutical standards, ensuring quality, efficacy, and safety for therapeutic use. With a proposed shelf life of two years from the date of manufacturing, the capsules were identified as size ‘2’ hard gelatin capsules with a pink opaque cap or any other colour and a clear transparent body, containing a mixture of white to off-white spherical pellets. Each capsule was formulated to contain 100 mcg of Levothyroxine Sodium I.P., with an acceptable label claim limit of 90%–110% (i.e., 90–110 mcg per capsule), ensuring consistent dosing. The fill weight was specified at 295 mg, with an allowable variation of ±7.5%, maintaining uniformity. The dissolution profile followed USP Apparatus No. 2 (paddle method) at 50 rpm in 500 ml solution, tested in two different pH conditions: pH 3.5, where the drug release was expected to be between 0–10% within 45 minutes, and pH 5.5, where Not Less Than (NLT) 70% was to be released within the same time frame, ensuring controlled and efficient absorption. The identification of Levothyroxine Sodium complied with I.P. standards, and the uniformity of content had to meet I.P. specifications, guaranteeing consistency in each dose. Additionally, impurity testing ensured that Liothyronine Sodium (impurity) did not exceed 2.0%, maintaining product purity and effectiveness. To preserve the stability and potency of the medication, storage conditions required protection from light and moisture, ensuring the product retained its integrity over its shelf life. This comprehensive specification data ensured that Levothyroxine Sodium Capsules met stringent pharmaceutical regulations, providing a reliable and safe option for patients requiring thyroid hormone therapy.
During the development of the product, the trials were taken at different concentrations of the drug to ascertain the robustness of process.
In an exemplary scenario, product development with respect to trials 1, 2, and 3 is provided. In Trial 1, the assay value was significantly low at 607.54 mcg/g, whereas Trials 2 and 3 recorded 998.8 mcg/g and 1010 mcg/g, Three trials were taken for the process development with different quantities of input materials to verify the process respectively, suggesting that Trial 1 produced a substandard( not substandard bur low assay) product. For dissolution at pH 3.5 over 45 minutes, the acceptable release range was 0–10%. Trial 1 exhibited no release, while Trial 2 and Trial 3 showed 7% and 5% release, respectively, both within the acceptable range. During the Batch development with respect to trials 1, 2, and 3 at pH 3.5, no significant release is identified, since the pellets are film coated .
In an exemplary scenario, for a production batch for Levothyroxine capsules, consisted of 10,000 capsules. Each capsule was designed to have a target weight of 295 mg, which included both Levothyroxine pellets and neutral filler pellets. The formulation ensured that each capsule delivered a precise dose of 100 mcg of Levothyroxine, with the filler pellets used to achieve the desired capsule weight while maintaining uniformity and dosage accuracy across the batch.
In an exemplary scenario, the standard, with a weight of 0.01056g, underwent a dilution process to 10ml, yielding five area measurements ranging from 407.481 to 408.23, with an average area of 407.8824, a standard deviation of 0.316747, and a relative standard deviation (RSD) of 0.077657, indicating high precision. The sample, weighing 1.04462g, was dissolved in 100ml, and two area measurements were recorded, averaging 448.7675. A calculation using the ratio of the sample average area to the standard average area, along with the standard weight, dilution factors, and a constant, resulted in a final concentration of 1024.189 mcg/g for the analyte in the sample. This indicates the concentration of the target compound in the sample based on the comparison to the standard.
The target weight of the capsule being 295 mg where Levothyroxine pellets along with the filler nutrient pellet showed 100mcg; 295mg (wt) per capsule. The Uniformity of Weight compliance (I.P),with a Weight Variation (limit: ±7.5 %) : 272.875 mg to 317.125mgs. A batch of 20 samples is provided:
The Uniformity of Weight compliance (I.P),with a Weight Variation (limit: ±7.5 %) : 272.875 mg to 317.125mgs were recorded. More particularly, recorded individual capsule weights were 296, 296, 297, 291, 295, 296, 298, 299, 300, 295 in one set and 296, 297, 295, 294, 296, 295, 296, 295, 294, 293 in a second set. All these weights fell within the acceptable range, indicating that the filling process was well-controlled and consistent. This consistency ensured dosage accuracy and met the quality standards for uniformity of weight as required by the I.P.
In an exemplary scenario, acid dissolution study was conducted. The dissolution data in an acidic medium (pH 3.5), inferred the analysis of a standard and a sample. The standard, with a weight of 0.01059g, underwent a series of dilutions, and its resulting areas were recorded over six trials, yielding an average area of 39.47967, a standard deviation of 1.22864, and a relative standard deviation (RSD) of 3.112082. A bracketing standard of 37.137 was also noted. The sample, taken at 500ml, was used to calculate a factor of 0.002475, which, when multiplied by a constant of 0.002504 and the sample areas (which are all zero), resulted in a percentage of 0.00% for all six trials and the average. (Fig. 2 & Fig. 3).
In an exemplary scenario, buffer dissolution study was conducted, where a standard solution was prepared using a known weight (0.01084g) of the drug substance. Fig.4 shows buffer dissolution of levothyroxine standard at a pH of 5.5.The standard solution was analyzed, and the peak area was recorded in six replicates (ranging from 58.619 to 61.638). The average peak area of the standard was 60.479, with a standard deviation of 1.233 and a relative standard deviation (RSD) of 2.039. One capsule was tested for dissolution. Samples were taken from the dissolution medium, diluted, and analyzed. The peak area for each sample was recorded in six replicates (ranging from 49.1 to 53.2). %. (Fig 5).
The Stability studies involved Accelerated Stability Studies and Real-time/Long-time Stability Studies. Also, the % area difference for peaks in Standard preparation and Sample solution reference to initial solution should be less than 2.0 indicates the stability of the product.
Analytical validation based on different validation parameters which showed Levothyroxine Sodium met all predefined criteria. System suitability tests revealed a %RSD of 1.30 for five replicate injections and a USP tailing factor of 1.14, both within the limit of 2.0. Specificity was confirmed, as no interference from placebo or diluent was observed. Precision was robust, with the %RSD for the area of six replicate standard injections at 1.31 and the % assay across six preparations at 0.7, both under the 2.0% threshold. Linearity was excellent, indicated by a correlation coefficient of 0.999. Additionally, range studies at different concentration levels showed %RSD values between 0.1 and 0.4, and accuracy tests confirmed mean recoveries between 90.0% and 110.0%. Robustness, filter paper influence, and analytical solution stability all passed, confirming the method's overall reliability and reproducibility.
The process validation encompassed several key evaluations to ensure overall product consistency and quality. The sieving process was assessed for pellet uniformity and yielded satisfactory results. Similarly, the drying process was evaluated to confirm uniform drying across all pellets, and it met the required standards. During the assay of active ingredients, the coating process was also examined to verify uniformity in drug content and dissolution, and it was found to be satisfactory. Collectively, these evaluations confirmed that each critical step in the manufacturing process was performing as intended, thereby validating the overall process and ensuring a consistent, high-quality product.While performing the assay of active ingredients the coating process evaluation was done for uniformity of drug content and dissolution. The process was found to be satisfactory.(Figure 9). Figure 8 illustrates a graphical representation representing the uniformity of contents in terms of levothyroxine standard. Fig. 10 represented the uniformity in terms of Levothyroxine bracketing standard, in accordance with an aspect of the present disclosure.
The product Levothyroxine Sodium Capsules from a batch with a batch size of 10,000 capsules was evaluated. The capsules, described as size “2” with a pink opaque cap and clear transparent body containing white and off-white spherical pellets, met the product description specification. Identification tests confirmed compliance with Levothyroxine Sodium IP. The average fill weight was 295 mg, and the uniformity of fill weight was within the ±7.5% limit. Each capsule was designed to contain 100 mcg of Levothyroxine Sodium (90–110% of the label claim) and measured 98.60 mcg, which is acceptable. Dissolution testing showed 0% release at pH 3.5 (within the 0–10% range) and 84.38% release at pH 5.5 (meeting the minimum requirement of 70%). Additionally, the impurity level of Liothyronine Sodium was 0.633% (below the 2.0% limit), and the uniformity of content averaged 94.649%, confirming overall compliance with specifications. Referring to Fig 7 of drawings representing the sample trials , where (a) and (b) represents Trial 1 and (c) and (d) representing Trial 2. The analysis involved comparing the peak area of a sample to a standard with a known concentration. During the Levothyroxine assay, a standard solution was prepared using 0.01084g of the standard substance. The peak area of the standard was measured six times, with an average of 574.831. The standard deviation (STD) was 7.503, and the relative standard deviation (RSD) was 1.305%, indicating good consistency in the standard measurements. Two trials were conducted using a sample weight of 2.99660g. The sample was diluted and analyzed, and the peak area was recorded. In Trial-1, the average peak area was 590.235, while in Trial-2, it was 511.853.
A calculation was performed to determine the amount of the substance per capsule. The standard concentration, dilutions, sample weight, and potentially a correction factor (92.51/100).
The formula used was:
(Sample area / Standard area) * 0.01059 / 100 * 1 / 10 * 100 / 0.9875 * 1000 * 1000 * 92.51/100)
The results indicated the calculated amount of the substance per capsule was: Trial-1: 98.94 mcg/Capsule and Trial-2: 97.99 mcg/Capsule
Figure 11 illustrates a graphical representation of comparative evaluation of dissolution and assay between Liothyronine and Levothyroxine. The presence of two distinct peaks indicates that the sample contains both Liothyronine and Levothyroxine, where the much larger peak for Levothyroxine suggests that it is present in a significantly higher concentration than Liothyronine in the sample. The sharp and well-defined nature of both peaks indicates good separation, suggesting the HPLC method effectively resolved these two compounds. (Fig.11) The high-performance liquid chromatography (HPLC) analysis, showed multiple peaks at various retention times. The most prominent peak appears at 6.033 minutes, indicating the highest concentration.
The study of the levothyroxine product is considered to be feasible in healthy males and females. For a 04-period study and the washout is long, we need to consider safety analysis with all the screening tests before every check-in and there may be more withdrawals/dropouts and this needs to be considered during sample size estimation, probably 30-35 %. Hence instead of a single four period study a two-period fed and a two period fasting study were also considered. This helped to reduce the study duration and also limit exposure of the subject to two times dosing.
The bio-analysis was found to be feasible (levothyroxine in serum) in single run on triple quad 5500. For the said study No. of analytes: 1; No. of metabolites: were MD/MV developed accordingly. Levothyroxine is present endogenously. Hence serum stripping is required with charcoal. Alternate approach could subtraction of the endogenous levels in blank samples were evaluated back conversion to be checked for metabolite liothyronine (L-T3) during method validation.
For the first pilots only total LT4 were measured. As per FDA guidance a suggested dose of 600µcg dose ensure adequate measurement of the analyte.
The bioavailability of the product was based on three distinct conditions. First, both the test and reference formulations were evaluated under fasting conditions. Second, their bioavailability was measured under fed conditions. Finally, the effect of food on the bioavailability of the test product was specifically examined. This comprehensive evaluation provided a clear understanding of how nutritional states impact the pharmacokinetic profiles of the formulations, allowing for a robust comparison between the test and reference products and ensuring that optimal dosing recommendations could be made based on varying food intake scenarios.
A crossover study was designed for a pilot pharmacokinetic (PK) evaluation. The study was structured as a four-treatment, four-period, four-sequence crossover, with both fed and fasting conditions. Under fed conditions, ARM 1 served as the reference and ARM 2 as the test product, while under fasting conditions, these roles were reversed. A 35-day washout period was employed based on a 100 mcg dose to minimize carryover effects between periods. Although no specific percentage difference between the test and reference products or maximum inter-subject coefficient of variation was provided, the study estimated a total sample size of 24 subjects to account for dropouts. PK sampling required 20 time points, with subjects remaining in-house for 2 days post-dose, and no ambulatory blood draws were performed. The primary evaluation parameters were Cmax, AUCT, and AUCI, with sample size estimation tailored to the pilot study requirements.
The PK parameter Cmax, AUCt and AUCi of test under fed performed better than the reference under fed, indicated the statistical significance.
Further trials with the product were conducted to process the Levothyroxine-Na Pellets into Multi-unit pellet system (MUPS) tablets.
The implementation set forth in the foregoing description do not represent all implementations consistent with the subject matter described herein. Instead, they are merely some examples consistent with aspects related to the described subject matter. Although a few variations have been described in detain above, other modifications or additions are possible. In particular, further features and/or variations can be provided in addition to those set forth herein. For example, the implementation described can be directed to various combinations and sub combinations of the disclosed features and/or combinations and sub combinations of the several further features disclosed above.

,CLAIMS:1. A composition comprising:
sugar pellets ranging from 1500 to 8500 grams of the composition;
levothyroxine sodium ranging from 2 to 10 grams of the composition;
sodium citrate ranging from 80-350 grams of the composition;
sodium lauryl sulphate ranging from 120-240 grams of the composition
starch ranging from 600-2200 grams of the composition;
sugar 1000 gms to 2000 gms grams of the composition;
lactose anhydrous ranging from 600- 3000 grams of the composition; and
acacia powder ranging from 50-350 grams of the composition.
2. The composition as claimed in claim 1, wherein composition is film coated to pellet, in the range of 270 mg to 320 mg to enclose in a capsule.
3. The composition as claimed in claim 1, further comprising a film coating solution that are selected from methacrylate polymer and a surfactant dissolved in a solvent.
4. The composition as claimed in claim 1, wherein the film-coated pellets are subjected to dissolution between pH 3.5 and pH 5.5 media solution in a USP type 2 dissolution apparatus.
5. The composition as claimed in claim 1, wherein levothyroxine pellets and filler neutral pellets forms 100mcg/capsule.
6. The composition as claimed in claim 1, where the uniformly sized pellets ranges from 1.00 mm to 0.710 mm size.
7. The composition as claimed in claim 1, wherein uniformity of fill weight of the pellet is at a variation of 7.5%.
8. The composition as claimed in claim 1, where the capsule material is selected from gelatin, collagen or hydroxypropyl methyl cellullose
9. A method (100) for preparing Levothyroxine Sodium IP pellets to enclose in capsules, comprising:
combining (102) sugar pellets, levothyroxine sodium, sodium citrate, starch, lactose anhydrous, sodium lauryl sulphate and acacia powder;
mixing (104) levothyroxine sodium, sodium citrate, sodium lauryl sulphate starch, lactose anhydrous, acacia powder in a geometric progression to create a homogenous coating powder;
loading (106) sugar pellets specific mesh size onto a coating pan;
setting (108) the coating pan to revolve at 10-100 RPM;
spraying (110) a measured volume of binding solution containing sugar and purified water onto sugar pellets intermittently;
coating (112) the pellets with the coating powder until exhausted;
unloading and drying (114) the coated pellets at 45 to 55 degrees Celsius for 8-16 hours; and
sieving (116) to obtain uniform-sized pellets of 1.00 mm to 0.710 mm.
10. The method as claimed in claim 8, further comprising film coating the pellets , wherein the film coating solution that are selected from methacrylate polymer and a surfactant dissolved in a solvent
11. The method (100) as claimed in claim 8, wherein the mesh size of the sugar pellets for loading on to coating pan is in the range of 0.600 mm to 0.500.
12. The method (100) as claimed in claim 8, wherein the pellets undergoes sieve test and analyzed for uniformity of drug content, loss on drying, bulk density and dissolution at pH 3.5 and 5. 5 media solution.