CLIAMS:We Claim:

1. An intermediate of one or more moisture sensitive APIs obtained by compacting one or more moisture sensitive APIs with one or more hydrophobic substances.

2. The intermediate of claim 1, wherein one or more moisture-sensitive APIs and one or more hydrophobic substances are compacted in a roller compactor.

3. The intermediate of claim 2, wherein one or more moisture-sensitive APIs and one or more hydrophobic substances are compacted at pressure of 30 to 90 kg/cm2 and at roller speed of 2-30 rpm.

4. A stable pharmaceutical composition comprising one or more intermediates of claim 1.

5. A process for the preparation of composition comprising one or more moisture-sensitive APIs, which process comprises the steps of:
(a) mixing one or more moisture sensitive APIs with one or more hydrophobic substances to form a mixture;
(b) compacting mixture of step (a) to form intermediates.
(c) milling the intermediates of step (b) to form granules;
(d) mixing the formed granules with one or more pharmaceutically acceptable excipients;
(e) lubricating thus formed granules with a pharmaceutically acceptable lubricant; and
(f) compressing the lubricated granules of step (e) to form a tablet;

6. An intermediate of any of the preceding claim, wherein the hydrophobic substance comprises magnesium stearate.

7. An intermediate of any of the preceding claim, wherein the ratio of moisture sensitive API to hydrophobic substance is about from 1:0.001 to 1:1 and preferably, the ratio is from 1:0.01 to 1:0.1.

8. The stable pharmaceutical composition of claim 4, wherein the composition retains at least 90% w/w of the potency of moisture-sensitive API when stored at 25°C and 40% relative humidity or at 400C and 25% relative humidity for 3 months.
,TagSPECI:4. Description

The present invention relates to a process for preparation of stable pharmaceutical compositions of moisture-sensitive active pharmaceutical ingredients. In particular, the present invention relates to a process for controlling the impurities of moisture-sensitive active pharmaceutical ingredients which may form during preparation of formulation. The pharmaceutical compositions may comprises one or more moisture sensitive APIs or combination of a moisture sensitive API with a non-moisture-sensitive API and one or more hydrophobic substances. The composition may provide immediate release or desired extended release of API when administered to a patient in need thereof.

One of the requirements for an acceptable pharmaceutical composition is that it must be stable. A stable pharmaceutical composition does not exhibit substantial decomposition of the active pharmaceutical ingredient during the time between the manufacture of the composition and its use by a patient.

The decomposition products of API are known as impurity which needs to be controlled in the finished product as per regulatory guidelines. According to International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), an impurity in a drug substance is defined as-“any component of the new drug substance that is not the chemical entity defined as the new drug substance”. The control of pharmaceutical impurities is currently a critical issue to the pharmaceutical industry and therefore ICH has provided a workable guideline regarding the control of impurities.

Impurities in pharmaceuticals are the unwanted chemicals that remain with the APIs, or develop during formulation, or upon aging of both API and formulated APIs to medicines. The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products.

Impurity profiling (i.e., the identity as well as the quantity of impurity in the pharmaceuticals), is now receiving critical attention from regulatory authorities. The different pharmacopoeias, such as the British Pharmacopoeia (BP) and the United States Pharmacopoeia (USP), have started to incorporate limits to allowable levels of impurities present in the APIs or formulations. There is an ever increasing interest in impurities present in API’s.

Recently, not only purity profile but also impurity profile has become essential as per various regulatory requirements. In the pharmaceutical world, an impurity is considered as any other organic material, besides the drug substance, or ingredients, arise out of synthesis or unwanted chemicals that remains with API’s. Impurity control in pharmaceutical products is a primary goal of drug development.

According to ICH, the maximum daily dose qualification threshold to be considered is as mentioned in table 1.
Table 1
Maximum Daily Dose Reporting Threshold Identification Threshold Qualification Threshold
≤ 2 g/day 0.05% 0.10% or 1.0 mg per day intake (whichever is lower) 0.15% or 1.0 mg per day intake (whichever is lower)
> 2g/day 0.03% 0.05% 0.05%

One of the sources of impurities is process of preparation of formulation i.e. during development. In particular, moisture-sensitive or oxidation prone APIs are more vulnerable to produce impurity if proper measures are not taken during development.

For most drugs, the reactive species consist of water (can hydrolyze some drugs or affect the dosage form performance). Hydrolysis is the common phenomenon for ester type of drugs. Humidity is one of the important key factors in case of hygroscopic compounds. It is detrimental to both bulk powder and formulated solid dosage form. The classic examples are ranitidine and aspirin.

Moisture-sensitive drugs present another challenge to formulators. Potential problems associated with these APIs include reduced flow properties, as well as changes in dissolution rates, chemical stability and physical stability (in terms of colour, for example). Some ways to protect moisture sensitive products involve humidity-controlled manufacturing conditions, protective packaging, moisture barrier film coating and, most importantly, selecting excipients that minimize moisture sensitivity.

Water of crystallization can participate in drug degradation when it is released from the crystalline state by actions such as grinding. This has been reported for the hydrolysis of sodium prasterone sulfate and ampicillin trihydrate. The degradation rate of ampicillin trihydrate increased with increasing grinding time. Similarly, cefixime trihydrate exhibit decreased stability as a result of grinding.

Additionally, excipients can affect drug stability by being a source of moisture. For example, owing to the high moisture content of polyvinylpyrrolidone and urea, aspirin hydrolysis was enhanced in solid dispersions with these excipients. Decreased drug stability caused by excipients having higher moisture-containing ability has been reported for tablets of aspirin and ascorbic acids and dry syrups of cephalexin.

It is known that, tablet blends may be dry mixed, dry-granulated or wet- granulated before tableting. The choice of the processing procedure, dry mixing, dry granulation, wet granulation, or some other granulation process, depends on the properties of the drug and the chosen excipients. Generally, a dry manufacturing process is thought to be preferable for moisture-sensitive drugs. Additionally, starch 1500® has been used to develop formulations with proven stability for many moisture-sensitive APIs, including aspirin and ranitidine.

PCT application number WO 2008/008057 discloses a stable pharmaceutical composition comprising a combination of moisture sensitive drug and a second pharmaceutically active ingredient. The formulation comprises at least one pharmaceutical excipient, wherein the moisture sensitive active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient.

US application number 2007/0281000 discloses the method to achieve good stability with a composition comprising the moisture-sensitive drug with a binder such as Copovidone, wherein the formulation/ composition is prepared using a wet granulation process, comprising wetting and then drying the composition at an elevated temperature.

To improve the stability of moisture sensitive drugs, water scavenger compounds may be incorporated into a tablet matrix. One such a water scavenger compound is the binder Copovidone (Plasdone S-630®), which binder is specifically recommended for moisture sensitive drugs. Wet-granulation processes have not been considered appropriate for moisture sensitive drugs since the very nature of these processes can include the presence of water/moisture.

However, reducing or eliminating degradation of API or in other words, controlling the impurity by using specialty excipients is expensive and unnecessarily increase the production cost. Moreover, one or more of these methods may not be suitable for certain APIs where process itself creates degradation prone environment such as release of water of crystallization during grinding.

Thus, there exists an enduring need to develop a robust and simple economical process, which eliminates the need of additional steps, expensive specialty excipients and sophisticated techniques for controlling impurity profile of moisture sensitive drugs.

The inventors of the present invention have surprisingly found that by preparing unique intermediates comprising one or more moisture-sensitive APIs and one or more hydrophobic substances, it is possible to effectively control the impurity level of moisture-sensitive APIs and enables formulator to have robust control over impurity profile. Moreover, the method controls the impurity efficiently in a reproducible manner.

The present invention relates to a process for preparation of an intermediate by compaction of one or more moisture-sensitive APIs and one or more hydrophobic substances. Further, the intermediates of the moisture sensitive APIs may be used for preparation of stable pharmaceutical compositions. In particular, the present invention relates to a process for preparation of pharmaceutical compositions of moisture sensitive APIs with reduced impurity level, wherein the API(s) is/are compacted with a hydrophobic substance. The composition may be coated with a functional moisture barrier coating or simple film coating. The optional film coating may be employed as abrasion resistant during handling or just to improve aesthetic appeal of the formulation. The composition may provide immediate release or desired extended release of API when administered to a patient in need thereof.

In one general aspect, there is provided an intermediate of one or more moisture sensitive APIs comprising one or more hydrophobic substances.

In another general aspect, there is provided a process for the preparation of stable intermediates comprising compacting one or more moisture sensitive APIs with one or more hydrophobic substances.

In another general aspect, there is provided a process for the preparation of intermediates of one or more moisture sensitive APIs, which process comprises steps of mixing one or more moisture sensitive APIs with one or more hydrophobic substances and compaction.

In another general aspect, there is provided a stable pharmaceutical composition comprising one or more intermediates of one or more moisture sensitive APIs prepared by compacting one or more moisture sensitive APIs with one or more hydrophobic substances.

In another general aspect, the intermediates are prepared by compaction of one or more moisture sensitive APIs with one or more hydrophobic substances by roller compaction, direct compression or slugging.

In another general aspect, the intermediates are in the form of granules, pellets, slugs or beads.

In another general aspect, the intermediates are further processed to form solid unit dosage forms.

In another general aspect, the intermediates are dry milled, dry granulated or wet granulated further to form granules.

In another general aspect, the granules are formed by granulating the intermediates with a binder solution and optionally with one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a tablet comprising plurality of intermediates of one or more moisture sensitive APIs, which intermediates are prepared by compacting the moisture sensitive APIs with one or more hydrophobic substances. The intermediates may be then milled to form granules and compressed to form a tablet.

In another general aspect, there is provided a process for the preparation of a tablet, which process comprises the steps of:
(a) mixing one or more moisture sensitive APIs with one or more hydrophobic substances to form a mixture;
(b) compacting the mixture of step (a) using roller compactor to form intermediates;
(c) milling the intermediates of to form granules;
(d) mixing the granules with at least one pharmaceutically acceptable excipient;
(e) lubricating the granules of step (d) with a lubricant, and
(f) compressing the lubricated granules to form a tablet.

In another general aspect, there is provided a process for the preparation of a tablet, which process comprises the steps of:
(a) mixing one or more moisture sensitive APIs with one or more hydrophobic substances to form a mixture;
(b) compacting the mixture of step (a) using roller compactor to form intermediates;
(c) milling the intermediate of step (b) to form granules;
(d) mixing the granules with at least pharmaceutically acceptable excipient;
(e) optionally mixing a non-moisture-sensitive API with granules of step (d);
(f) lubricating the granules formed in step (d) or (e) with a lubricant;
(g) compressing the lubricated granules step (f) to form a tablet;
(h) optionally, coating the tablet with a film forming polymer or release modifying substance, and
(i) optionally, coating the tablet formed in step (g) or (h) with a moisture barrier coating.

In another general aspect, there is provided a process for the preparation of a solid unit dosage form, which process comprises the steps of:
(a) mixing one or more moisture sensitive APIs with magnesium stearate;
(b) compacting the mixture to form intermediates;
(c) milling the intermediates to form granules;
(d) mixing the granules with pregelatinised starch, dicalcium phosphate dihydrate & microcrystalline cellulose;
(e) lubricating the granules of step (d) with magnesium stearate, and
(f) formulating the intermediates in a suitable solid unit dosage form.

In another general aspect, there is provided a stable pharmaceutical composition comprising one or more intermediates of cefixime or salts thereof prepared by compacting cefixime with one or more hydrophobic substances.

In another general aspect, there is provided a process for the preparation of a tablet, which process comprises the steps of:
(a) mixing one or more moisture sensitive APIs with one or more hydrophobic substances to form a mixture;
(b) compacting the mixture of step (a) using roller compactor to form intermediates;
(c) milling the intermediate of step (b) to form granules;
(d) mixing the granules with at least pharmaceutically acceptable excipient;
(e) optionally mixing a non-moisture-sensitive API with granules of step (d);
(f) lubricating the granules formed in step (d) or (e) with a lubricant;
(g) filling the lubricated granules of step (f) in a capsule.

In another general aspect, the ratio of the moisture sensitive API to the hydrophobic substance is in the range of about 1:0.001 to 1:10 and preferably, about 1:0.01 to 1:1.

In another general aspect, the pharmaceutical composition comprising plurality of intermediates of moisture sensitive APIs prepared in accordance with the present invention retains at least 90% w/w of the potency of said API when stored at 25°C and 40% relative humidity or at 400C and 25% relative humidity for 3 months.

The composition in accordance with the present invention comprises one or more intermediates prepared by compaction of one or more moisture-sensitive APIs and one or more hydrophobic substances. In an embodiment, the compaction may be done in a roller compactor at a pressure between 30 to 90 kg/cm2 and at roller speed of 2-40 rpm, preferably at a pressure between 50 to 70 kg/cm2 and at roller speed of 10-15 rpm.

The term "intermediate" used throughout the specification shall apply to mean a pharmaceutical composition which is not administered directly, but is instead converted into an applicable oral dosage form by means of suitable methods, such as granulation and/or compression.

The term "moisture-sensitive API" used throughout the specification shall apply to the active pharmaceutical ingredients which undergo change in its chemical and/or physical properties, preferably degrades in the presence of water or moisture. Suitable examples of the moisture sensitive drugs includes, but not limited to cefixime, acetyl salicylic acid (asprin), procaine, cocaine, physostigmine, tetracaine, methyl dopate, dibukucaine, ergotamine benzyl-penicillin sodium, chloramphenicol, nitrazepan, chlordiaze-poxide, penicillins and cephalosporins. Other active materials which may advantageously be used in the processes of this invention include water soluble vitamins, bronchodilators such as salbutamol, highly. Further moisture-sensitive active materials include water soluble materials that form highly viscous solutions when dissolved in water. Examples of such materials are the sugars, including sucrose, dextrose, fructose and hydrophobic polymers such as cellulose derivatives.

The term “compaction” used throughout the specification refers to various methods known in the art which results in increase in the density and reduction of porosity of the ingredient or mixture of several ingredients by the application of pressure. The application of pressure is preferably done by mechanical means between two rolling drums of a machine known as roller compactor.

The term "mixing" used throughout the specification refers to a process of combining substances with the aim of achieving a substantially homogeneous distribution of different substances by the effect of mechanical forces. Mixing for the purposes of the invention is performed in conventional mixing devices, such as roll mixers, shaking mixers, free-fall mixers, shear mixers, ploughshare mixers, planetary mixing kneaders, Z or sigma kneaders or fluid or intensive mixers.

The term “hydrophobic substance” used throughout the specification refers to any substance having low affinity towards water.

The intermediates of the moisture sensitive API of the present invention may be developed in the form granules, pellets, mini-tablets, and slugs.

The intermediates of the moisture sensitive API may be developed in the form pharmaceutical compositions such as granules, pellets, capsule, tablet, caplet or a mini-tablet. Preferably the composition is in the form of a tablet.

In one embodiment, the composition in accordance of the present invention comprises one or more moisture-sensitive API and a hydrophobic substance, wherein the ratio of API to hydrophobic substance is about from 1:0.001 to 1:10 and preferably, the ratio is from 1:0.01 to 1:1.

In another embodiment, the intermediates are prepared by compacting one or more moisture-sensitive API with one or more hydrophobic substances in a roller compactor preferably a pressure between 50 to 70 kg/cm2 and at roller speed of 10-15 rpm.

In another embodiment, the pharmaceutical composition comprising plurality of intermediates of moisture sensitive APIs prepared in accordance with the present invention retains at least 90% w/w of the potency of said API when stored at 25°C and 40% relative humidity or at 400C and 25% relative humidity for 3 months.

The process for the preparation of intermediates of one or more moisture sensitive API, which process comprises steps of mixing one or more moisture sensitive APIs with one or more hydrophobic substances and compaction.

In another embodiment, the process of preparing the intermediates of one or more moisture sensitive APIs comprises a step of compacting the moisture sensitive APIs with one or more hydrophobic substances. The intermediates may be then milled to form granules and compressed to form a tablet.

In an embodiment, the compaction is performed by various methods known to person skilled in the art such as roller compaction, direct compression or slugging.

The intermediates further may be processed to form granules, pellets, slugs or beads.

The intermediate obtained by the process of present invention may be milled to form granules. The oscillating granulator is suitable for such operation. The formed intermediates may be passed through # 60 to obtain above # 60 portion which is called as granules. The below # 60 portion called as fines may be collected and repeated the compaction step using roller mill so that at least 50 to 60 % of fraction of above 60 # granules are obtained.

In another embodiment, the granules may be formed by granulating the intermediates, obtained by the process of invention, with a binder solution. The intermediates optionally may be granulated with one or more pharmaceutically acceptable excipient.

The intermediates are further used to prepare stable pharmaceutical composition, wherein the intermediates are milled to form granules which granules optionally with one or more pharmaceutically acceptable excipients are compressed to form tablet.

In another embodiment, there is provided a process for the preparation of a solid unit dosage form, which process comprises the steps of:
(a) mixing one or more moisture sensitive APIs with one or more hydrophobic substances;
(b) compacting the mixture to form intermediates;
(c) milling the intermediates to form granules;
(d) mixing the formed granules with at least one pharmaceutically acceptable excipient;
(e) lubricating granules of step (d) with a lubricant; and
(f) formulating the intermediates in a suitable solid unit dosage form.

In another embodiment, the intermediate is used to prepare stable pharmaceutical composition in the form of tablet which tablet is optionally coated with a film forming polymers or one or more release modifying substances.

In another embodiment, the stable pharmaceutical composition is in the form of tablet which tablet is optionally coated with a moisture barrier coating, which may optionally further coated with film coating.

In another embodiment, there is provided a process for the preparation of a solid unit dosage form, which process comprises the steps of:
(a) mixing one or more moisture sensitive APIs with one or more hydrophobic substances;
(b) compacting the mixture to form intermediates;
(c) milling the intermediates to form granules;
(d) mixing the formed granules with at least one pharmaceutically acceptable excipient;
(e) lubricating granules of step (d) with a lubricant; and
(f) filling the powder of step (f) in a capsule.

The composition of the present invention may comprise one or more pharmaceutically acceptable excipients selected from, but not limited to, diluent, disintegrant, glidant, lubricant, antioxidant and stabilizing agent.

The hydrophobic substances which can be used may be selected from the group consisting of lipophilic agents (water-insoluble polymers) selected from the group consisting of waxes such as white wax, bees wax, carnauba wax and the like, metal salts of fatty acids such as magnesium stearate, calcium stearate and the like, fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g. palmitin, stearin, behenic, laurin, myristin, hydrogenated vegetable, castor, cottonseed oils, glyceril behenate and the like; ethyl cellulose; acrylic acid polymers and copolymers (available commercially under Eudragit® brand); and mixtures thereof; and the inert agents are selected from the group consisting of thermoplastic polymers, which are insoluble and indigestible in the gastrointestinal fluids, such as polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polymethylmethacrylates, polyamides, silicones, ethyl cellulose, polystyrene, and mixtures thereof.

The release modifying substances which can be used may be selected from the group consisting of hydrophilic agents (e.g. water-soluble polymers), lipophilic agents (water-insoluble polymers) and inert matrix agents, wherein the hydrophilic agents are selected from the group of pharmaceutical excipients which generate a gel in contact with water, including cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like; noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone; polyvinylacetate polymers and copolymers; acrylic acid polymers and copolymers, polyethylene oxide and mixtures thereof; the lipophilic agents are selected from the group consisting of waxes such as white wax, bees wax, carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g. palmitin, stearin, behenic, laurin, myristin, hydrogenated vegetable, castor, cottonseed oils, glyceril behenate and the like; ethyl cellulose; acrylic acid polymers and copolymers (available commercially under Eudragit® brand); and mixtures thereof; and the inert agents are selected from the group consisting of thermoplastic polymers, which are insoluble and indigestible in the gastrointestinal fluids, such as polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polymethylmethacrylates, polyamides, silicones, ethyl cellulose, polystyrene, and mixtures thereof.

Diluents increase the bulk of a solid pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example. Exemplary disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Exemplary excipients that may function as glidants include, but not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

A stabilizing agent can be added to the composition to stabilize the product during production and during storage of the formulation. Exemplary stabilizing agent include butylated hydroxy anisole, butylated hydroxy toluene, citric acid anhydrous or hydrous, benzoic acid, lanoline, sulphated derivatives, Ortho-phosphoric acid alone or in combinations there of.

An antioxidant can be added to the composition to eliminate or reduce oxidation of the product during production and during storage of the formulation. Exemplary antioxidant include butylated hydroxytoluene, butylated hydroxyanisole, DL-alpha-tocopherol, propyl gallate, octyl gallate, ethylenediamine tetraacetate, ascorbyl palmitate, acetyl cysteine, ascorbic acid, sodium ascorbate, fumaric acid, lecithin and the like and mixtures thereof. The antioxidant in the dosage form ranges from 0.1% to 15% by weight of the composition.

The composition of the present invention may be coated with moisture barrier coating like Opadry AMB or with simple film coating of hydrophilic polymer like HPMC.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1:
Table 1
Sr.No. Ingredients % w/w
Intragranular
1 Cefixime trihydrate equivalent to Cefixime 10-60
2 Dicalcium phosphate dihydrate 1-40
3 Microcrystalline cellulose 0.1-10
4 Magnesium stearate 0.01-5
Extragranular
5 Pregelatinised Starch 5-40
6 Microcrystalline cellulose 5-60
7 Dicalcium phosphate dihydrate 10-60
8 Magnesium stearate 0.05-5
Coating
9 Opadry 03G58632 0.1-10
Tablet 100

Process: Cefixime trihydrate was mixed with dicalcium phosphate dehydrate, microcrystalline cellulose and magnesium stearate using roller compactor at pressure between 20 to 90 kg/cm2 and roller RPM 5 to 30 to form intermediate. The intermediate thus formed were collected and milled using oscillating granulator. The milled intermediates were passed through # 60 to obtain above # 60 portion called as granules. The below # 60 portion called as fines were collected and compaction step was repeated till 50 to 60 % of fraction of above 60 # granules were obtained. The granules thus formed were mixed in double cone blender with co-sifted pregelatinised starch, dicalcium phosphate dihydrate & microcrystalline cellulose. The blend was lubricated with pre-sifted magnesium stearate in a double cone blender for 3 minutes and compressed using capsule shaped punches with beveled edges and a divided score line on each side.

Example 2:
Table 2
Sr. No. Ingredients % w/w
Intragranular
1 Cefixime trihydrate equivalent to Cefixime 10-60
2 Dicalcium phosphate dihydrate 10-80
3 Microcrystalline cellulose 1-10
4 Pregelatinised Starch 1-10
5 Magnesium stearate 0.1-5
Extragranular
6 Microcrystalline cellulose 1-20
7 Magnesium stearate 1-20
Coating
8 Opadry 03G58632 0.1-10
Tablet 100

Process: Cefixime trihydrate was mixed with dicalcium phosphate dihydrate, pregelatinised Starch, microcrystalline cellulose and magnesium stearate and compacted using roller compactor at pressure between 20 to 90 kg/cm2 and roller RPM 5 to 30 to form intermediate. The intermediate thus formed were collected and milled using oscillating granulator. The milled intermediates were passed through # 60 to obtain above # 60 portion called as granules. The below # 60 portion called as fines were collected and compaction step was repeated till 50 to 60 % of fraction of above 60 # granules were obtained. The granules thus formed were mixed in double cone blender with microcrystalline cellulose. The blend was lubricated with pre-sifted magnesium stearate in a double cone blender for 3 minutes and compressed using capsule shaped punches with beveled edges and a divided score line on each side.

Example 3:
Table 3
Sr. No. Ingredients % w/w
Intragranular
1 Cefixime trihydrate equivalent to Cefixime 10-40
2 Magnesium stearate 0.1-10
Extragranular
3 Dicalcium phosphate dihydrate 10-60
4 Pregelatinised Starch 5-40
5 Microcrystalline cellulose 5-40
6 Magnesium stearate 0.1-10
Coating
7 Opadry 03G58632 0.1-10
Tablet 100

Process: Cefixime trihydrate was mixed with magnesium stearate and compacted using roller compactor at pressure between 20 to 90 kg/cm2 and roller RPM 5 to 30 to form intermediate. The intermediate thus formed were collected and milled using oscillating granulator. The milled intermediates were passed through # 60 to obtain above # 60 portion called as granules. The below # 60 portion called as fines were collected and compaction step was repeated till 50 to 60 % of fraction of above 60 # granules were obtained. The granules thus formed were mixed in double cone blender with dicalcium phosphate dehydrate, pregelatinised starch and microcrystalline cellulose. The blend was lubricated with pre-sifted magnesium stearate in a double cone blender for 3 minutes and compressed using capsule shaped punches with beveled edges and a divided score line on each side.

The products from all above mentioned three examples were evaluated for highest individual impurity, total unknown impurity and total related substances. Forced degradation study was not performed for trial one as initial impurities level was very high.
Impurity level:
Sr.No Condition Degradation products Trial 1 Trial 2 Trial 3
1 Initial Highest individual impurity 0.617 0.367 0.144
Total unknown 2.009 0.989 0.496
Total related substances 2.009 0.989 0.496

2 Forced Degradation(60oC for 10 days) Highest individual impurity - 3.763 2.659
Total unknown - 9.626 6.668
Total related substances - 9.626 6.668