Claims:1. A process for preparing HPMC based hard capsule shell, the process comprising the steps of:
(i) preparing a dispersion of HPMC in acidified aqueous media having a temperature of about 75-85°C;
(ii) cooling the above dispersion, a temperature below 20 oC to obtain a solution;
(iii) adding a dilute acid to the above blend to adjust the pH about 3.5 to about 4.5 and stirring to form a uniform and clear solution;
(iv) optionally blending step (ii) solution with one or more excipients/additives/ colourants/ pigments;
(v) pouring the solution of step (iv) into a dipping dish of capsule manufacturing machine;
(vi) dipping the metal pins into the HPMC solution to form a thin gelled film on pin’s surface;
(vii) drying the pins at a suitable temperature to obtain caps and bodies of two-piece hard shells and
(viii) removing caps and bodies from the pins and joining to form hard capsule shells.
2. The process according to claim 1, wherein the HPMC grade has a viscosity in the range of about 3 to about 15 cPs.
3. The process according to claim 1, wherein the HPMC is 2910 chemistry.
4. The process according to claim 1, wherein the dispersion comprises HPMC in an amount of about 10% to about 30% by weight based on total weight of the solution.
5. The process according to claim 1, wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid, formic acid, acetic acid, lactic acid, tartaric acid, oxalic acid, citric acid and mixtures thereof.
6. The process according to claim 5, wherein the acid is hydrochloric acid.
7. The process according to claim 6, wherein the hydrochloric acid has a molarity of 0.1M.
8. The process according to claim 7, wherein said acid is present in an amount of about 0.05% to about 0.1 weight % based on weight of HPMC.
9. The process according to claim 1, wherein the bath solution in step (v) is maintain below 25 oC while following thermo gelation process.
10. The process according to claim 1, wherein the dipping pin temperature in step (vi) is maintained between 70 oC to 100 oC while following thermo gelation process.
11. The process according to claim 1, wherein the pins in step (viii) are dried at a temperature of about 80oC to 50oC while following thermo gelation process.
12. The process according to claim 1, wherein the aqueous media is water.
13. The process according to claim 1, wherein the capsule shell may comprise one or more additives selected from the group consisting of gelling agents and co-gelling agents while following cold gelation process.
14. The process according to claim 13, wherein the gelling agents may consists of carrageenan, pectin, gellan gum, curdlan, tamarind seed polysaccharides and agar. In a preferred embodiment, the gelling agent is carrageenan.
15. The process according to claim 13, wherein the capsule shell may comprise one or more additives selected from the group consisting of co-gelling agents.
16. The process according to claim 15, wherein the co gelling agent can be selected from one or more of potassium, ammonium, sodium and calcium ions, for example, potassium chloride, potassium phosphate, potassium acetate, calcium chloride, sodium citrate and ammonium chloride. In a preferred embodiment, the co-gelling agent is potassium ion.
17. The process according to claim 1, wherein the bath solution in step (v) is maintain between 35 oC to 50 oC while following cold gelation process.
18. The process according to claim 1, wherein the dipping pin temperature in step (vi) is maintained below 35 oC while following cold gelation process.
19. The process according to claim 1, wherein the pins in step (viii) are dried at a temperature of about 20oC to 50oC while following cold gelation process.
20. The process according to claim 1, wherein the resultant capsules have dissolution and mechanical properties comparable to conventional HPMC capsules.
21. The process according to claim 1, wherein the resultant capsules have enhanced clarity in comparison to conventional HPMC capsules.
22. The process according to claim 1, wherein the resultant capsules have enhanced whiteness in comparison to conventional HPMC capsules.
, Description:
FIELD OF THE INVENTION
The present invention relates to a process for preparing HPMC based hard capsule shells that exhibit enhanced transparency in transparent capsules and enhanced whiteness in opaque capsules. The process comprises the preparation of low molecular weight HPMC solution in a pH range of about 3 to 5 and manufacturing capsules thereof.

BACKGROUND OF THE INVENTION

HPMC capsule shells are nontoxic vegetarian capsule shells which are manufactured from Non animal origin material HPMC and are widely used in food and pharmaceutical industry. HPMC shells have several advantages over gelatin such as non-animal origin, do not exhibit cross-linking (one of the major issues with gelatin shells), contain less moisture, less brittle, and less susceptible to microbial growth. These attributes positioned HPMC capsules for use in a broader range of drug products, nutritional products and formulations. Specifically, HPMC capsules enables the incorporation of ingredients that are hygroscopic, sensitive to moisture or chemically incompatible with gelatin.

However, hydroxypropyl methyl cellulose (HPMC) lacks self-gelling ability at lower temperatures (<50oC), therefore capsules are often manufactured with the help of an additional setting agent consisting of another polymer. In another approach, HPMC capsules are manufactured by utilizing the thermo-gelling property of this polymer at higher temperatures (>55oC).

Generally, for non-animal origin capsule manufacturing, low molecular weight HPMC is used which is pale yellow in colour. The yellowing is attributed to the chromophore groups present at the HPMC chain ends. The population of chain ends increases as the molecular weight gets lowered and yellowness become very prominent for low molecular weight HPMCs. The use of low molecular weight HPMCs imparts pale yellowness and/or less brightness to the capsule products. In white opaque capsules this yellowness often interferes with the white light scattering and make them less bright.

The International Patent Application WO 01/18062 discloses a process for depolymerization of cellulose ethers in a concentrated aqueous slurry in the presence of an oxidizing agent to produce low molecular weight cellulose ethers of high purity and whiteness.

U.S. Patent No. 4,061,859 discloses a method of contacting a cellulose ether with gaseous HCl or another hydrogen halide gas and inhibiting the yellowing of the depolymerized product with sulfur dioxide gas.

U.S. Patent No. 8,569,479 discloses that low molecular weight cellulose ethers of low yellowing or discoloration can be achieved if the partial depolymerization is conducted in a diluent which comprises at least 50 percent of an organic hydroxylic compound having at least one hydroxy group and at least two carbon atoms.

All the above requires special equipment or process steps during manufacturing of HPMC powder.

The inventors of the present application have found an alternative process that does not require any additional investment in machinery or equipment and manufactures hydroxypropyl methyl cellulose (HPMC) based hard capsule shells exhibiting extra transparency in transparent capsules and extra whiteness in opaque capsules.

SUMMARY OF THE INVENTION
The present inventors have surprisingly found that preparation of low molecular weight HPMC solution in acidic medium/condition drastically reduced yellowing in the transparent capsules and produce clear transparent hard capsule shells. Furthermore, the acidification step produces yellow tint free and extra whiteness in case of opaque capsules. It was found that optimal discoloration or removal of yellowness is achieved at a pH of about 3 to 5, preferably between 3.5 to 4.5.

In one aspect of the invention, there is provided a process of preparing HPMC hard capsule shells having enhanced transparency, the process comprising the steps of:
(i) preparing a dispersion of HPMC in an acidic aqueous medium having a temperature of about 75-85oC;
(ii) cooling the above dispersion below 20oC to obtain a solution;
(iii) adding a small quantity of dilute acid to adjust the pH between about 3.5 to about 4.5 to step (ii) solution with continuous stirring to form a uniform and clear solution;
(iv) re heating the above solution to a desired dipping temperature preferably below 25oC;
(v) pouring the above solution into a dipping dish of capsule manufacturing machine;
(vi) dipping the hot metal pins into the HPMC solution to form a thin thermally gelled film on pin’s surface;
(vii) drying the pins at a temperature range of 80oC - 50oC slowly to obtain caps and bodies of two-piece hard shells and
(viii) removing the caps and bodies from the pins and joining the two to form clear transparent hard-shell capsules.

In another aspect of the invention, there is provided a process of preparing HPMC hard capsule shells having enhanced transparency, the process comprising the steps of:
(i) preparing a dispersion of HPMC in an acidic aqueous medium having a temperature of about 75-85oC;
(ii) cooling the above dispersion below 20oC to obtain a solution;
(iii) adding a small quantity of dilute acid to adjust the pH between about 3.5 to about 4.5 to step (ii) solution with continuous stirring to form a uniform and clear solution;
(iv) Adding pre-determined quantity of gelling and co gelling agents;
(v) Stirring the complete composition for achieving homogeneity;
(vi) re heating the above solution to a desired dipping temperature;
(vii) pouring the above solution into a dipping dish of capsule manufacturing machine;
(viii) dipping the metal pins of temperature below 35 oC into the hot HPMC solution to form a thin cold gelled film on pin’s surface;
(ix) drying the pins at a temperature range of 25o- 50 oC slowly to obtain caps and bodies of two-piece hard shells and
(x) removing the caps and bodies from the pins and joining the two to form clear transparent hard-shell capsules.

In one of the embodiments, there is provided a process of preparing low molecular weight HPMC hard capsule shells with enhanced transparency, the process comprising the steps of:
(i) preparing a dispersion of HPMC in an acidic aqueous medium having a temperature of about 75-85oC;
(ii) adding suitable amount of silicon dioxide to above solution to form a uniform blend;
(iii) adding dilute hydrochloric acid to adjust the pH between about 3.5 to about 4.5 and continue stirring until decolouration of solution is observed;
(iv) defoaming the above solution under slow stirring for about 1 hour and
(v) re heating the above solution to a desired dipping temperature preferably below 25oC;
(vi) pouring the above solution into a dipping dish of capsule manufacturing machine;
(vii) dipping the hot metal pins into the HPMC solution to form a thin thermally gelled film on pin’s surface;
(viii) drying the pins at a temperature range of 80o-50oC slowly to obtain caps and bodies of two-piece hard shells and
(ix) removing the caps and bodies from the pins and joining the two to form clear transparent hard-shell capsules.

In another aspect, there is provided a process of preparing low molecular weight HPMC hard opaque capsule shells having enhanced whiteness, the process comprising the steps of:
(i) preparing a dispersion of HPMC in an acidic aqueous medium having a temperature of about 75-85oC;
(ii) cooling the above dispersion below 20 oC to obtain a pale-yellow viscous solution;
(iii) blending the solution of step (ii) with one or more inert materials/pigments;
(iv) adding a small quantity of dilute hydrochloric acid to above blend to adjust the pH between about 3.5 to about 4.5 and stirring continuously to form a uniform solution;
(v) re heating the above solution to a desired dipping temperature preferably below 25oC;
(vi) pouring the above solution into a dipping dish of capsule manufacturing machine;
(vii) dipping the hot metal pins into the HPMC solution to form a thin thermally gelled film on pin’s surface;
(viii) drying the pins at a temperature range of 80oC - 50oC slowly to obtain caps and bodies of two-piece hard shells and
(ix) removing the caps and bodies from the pins and joining the two to form hard-shell capsules having enhanced whiteness.

In one of the embodiments, there is provided a process of preparing low molecular weight HPMC hard capsule shells having extra whiteness, the process comprising the steps of:
(i) preparing a dispersion of HPMC in an acidic aqueous medium having a temperature of about 75-85oC and cooling the above dispersion below 20oC to obtain a pale-yellow viscous solution;
(ii) adding suitable amounts of silicon dioxide and titanium dioxide to above solution to form a uniform blend;
(iii) adding dilute hydrochloric acid to adjust the pH about 3.5 to about 4.5 and continue stirring until decolouration of solution is observed;
(iv) Adding pre-determined quantity of gelling and co gelling agents;
(v) defoaming the above solution under slow stirring for about 1 hour and
(vi) re heating the above solution to a desired dipping temperature;
(vii) pouring the above solution into a dipping dish of capsule manufacturing machine;
(viii) dipping the metal pins of temperature below 35 oC into the hot HPMC solution to form a thin cold gelled film on pin’s surface;
(ix) drying the pins at a temperature range of 25o- 50 oC slowly to obtain caps and bodies of two-piece hard shells and
(x) removing the caps and bodies from the pins and joining the two to form hard-shell capsules having enhanced whiteness.

In yet another aspect, the present invention provides a HPMC hard capsule wherein the dispersion of HPMC is prepared in an acidic aqueous medium having a temperature of about 80oC.

In yet another aspect, the present invention provides a HPMC hard capsule comprising a capsule shell as defined above and one or more active substances filled therein optionally mixed with one or more pharmaceutically acceptable excipients.

In one of the embodiments of above aspects, suitable compounds that may be filled in the HPMC capsule shell include pharmaceuticals, vitamins, and nutrients etc. including hygroscopic materials.

In still another aspect, the disclosed invention relates to HPMC hard capsule shells as disclosed herein for use in manufacture of dosage forms suitable for administration to a subject in liquid or in solid form.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1. shows the images of the HPMC capsules produced (A) without adding dilute HCl and (B) with the addition of dilute HCl.

DETAILED DESCRIPTION
Any numerical range recited herein, includes all values from the lower value and the upper value, in increments of one unit, provided that there is a separation of at least two units between any lower value and any higher value.

Capsules are well-known dosage forms that normally consist of a shell filled with one or more specific substances. The shell may be a soft or, as in this invention, a hard-shell comprising film-forming polymer(s) such as modified celluloses. The HPMC hard capsules of the present invention do not structurally depart from the conventional definition of hard capsules.

The HPMC hard capsules of the present invention dissolve at a rate comparable to conventional gelatine capsules. Such capsules can be manufactured at an industrial scale with process speed comparable to gelatine capsules. Their mechanical properties are better than those of conventional gelatine capsules since they are less brittle, particularly under extremely dry atmosphere. These are extra transparent and extra white in visual appearance.

The HPMC based capsule shell in the present invention is prepared by a well-known dip molding technique as used in the manufacture of conventional capsule shells. In this process, pin molds are dipped into a film forming composition. By gelling the film forming polymer on the pin, a film is formed that is subsequently dried on the pin, to obtain capsule shells. The shells are then stripped of the pins and cut to a desired length. Thus, capsules caps and bodies are obtained that can later be filled with a substance and joined such that a filled capsule is obtained.

Typically, hard capsule dip-molding manufacturing processes encompass an additional step of lubricating the pins to make it easier to strip the capsule shells from the pins. Lubrication is normally achieved via the application of a demolding agent to the pins surface.
Low molecular weight HPMC has a molecular weight such that a two percent aqueous solution at 20°C has a viscosity of about 50 cP or less, preferably about 3 to about 15 cP, and most preferably about 3 to about 6 cP in a two percent aqueous solution at 20°C.
As used herein, the term “dip molding method” refers to dipping a pin shapes as a capsule cap or capsule body in an aqueous solution containing the capsule composition.

The present manufacturing process involves the dissolving low molecular weight HPMC in water to form a viscous solution and dip molding into the hard-shell capsules. The dip molding process involves dipping metal pins into the HPMC solution and allowing the solution to form a thin gelled wet mass on pin surface. Slowly drying the same to obtain films around the pins to result hemi-oval shells called caps and bodies of two-piece hard shells that are subsequently removed from the respective pins and joined to form hard capsules.

Both hot pin/cold solution and cold pin/hot solution processes are possible.

The typical process is as follows
- dispersing in acidic hot water and cooling to below 20oC to obtain a pale-yellow viscous solution;
- adding other ingredients ((such as silicon dioxide (SiO2), titanium dioxide (TiO2) for white capsules etc.)) as per the requirements and mixing properly;
- adding dilute HCl to adjust the solution pH to the range of 3.5 to 4.5 and stirring mechanically to ensure uniform distribution until decolouration of the solution is observed;
- defoaming the prepared HPMC solution under vacuum and slow stirring for 1 hour;
- pouring the clear solution into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at pre-set temperatures;
- performing the dip molding process by a process similar to that for the production of size # 0 HPMC capsules ;
- obtaining extremely clear and transparent capsules (no TiO2 added) or extra white opaque capsules (with TiO2 added).

The modified process is very similar to the conventional HPMC capsule manufacturing process and therefore does not require any additional investment in machinery or equipment.
In an embodiment, the dispersion contains between 10% and 30% of HPMC by weight based on the total weight of the solution.

In the present invention, the acid is added in an amount sufficient to provide HPMC solution a pH of about 3 to about 5, more preferably about 3.5 or about 4.0 or about 4.5. The acid content will vary according to the type and/or strength of the acid and typically range from about 0.05% to about 0.1 weight % based on the weight of HPMC.

Preferred acids are hydrochloric acid, formic acid, acetic acid, lactic acid, tartaric acid, oxalic acid, citric acid and mixtures thereof.

In a preferred embodiment, the acid used is dilute hydrochloric acid (0.1M HCl) and is added in the concentration of less than 0.1%, preferably about 0.08 weight % based on the weight of HPMC shell.

For obtaining coloured capsules, at least one inert non-toxic pharmaceutical grade or food grade pigment between 0.001 and 5% by weight based on the shell weight can be incorporated in the capsule shell.

In an embodiment, the capsule shell contains titanium dioxide.
Titanium dioxide is particularly useful as a pigment component because it is non-toxic, highly opaque and especially a useful opacifier, providing white colour and having good hiding power and tinctorial strength.
In an embodiment, the capsule shell includes a colouring agent. The colouring agent may be any FD & C lake, D & C lake, dye (water soluble or water insoluble) approved for ingestion by the U.S. Federal Drug Administration or similar governmental regulatory body.

In an embodiment, the HPMC capsule shell contains one or more plasticizers between 0 and 5%, by weight based on the shell weight. To avoid excessive softness, the amount of plasticizer included should be kept to minimum. Examples of suitable plasticizers include but are not limited to glycerine, propylene glycol, polyethylene glycol, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, tributyl citrate, triethyl citrate, acetylated monoglyceride or hydroxypropyl glycerine.

In another embodiment, the HPMC capsule shell contains one or more antibacterial agents between 0 and 2 % by weight based on the shell weight.

In another embodiment, the HPMC capsule shell contains one or more flavouring agents between 0 and 2% by weight based on the shell weight.

During the thermo gelation molding process, the temperature range of the pre-heated pins is about 70oC to about 100oC meaning that this is the pin temperature when pins are dipped. This temperature is chosen according to the chosen capsule size. The smaller the pin dimension, the higher the temperature and vice versa in case of larger pin size.

The pins, after being withdrawn from the dipping solution can be turned from a “top-down” dipping position to a “top-up” position according to capsule molding process.

The objective of the drying step is to reduce the water content in the wet capsule shells on the pins to less than 10% by weight based on the weight of dried capsule shells.

In another embodiment, the HPMC capsule shell contains about 2 to about 8 weight % of water based on the shell weight.

In cold gelling process, the HPMC capsule shell contains one or more gelling and co-gelling agents between 0.1 and 5% by weight based on the shell weight. Examples of suitable gelling agents include carrageenan, pectin, gellan gum, curdlan, tamarind seed polysaccharides, gelatin and agar. In a preferred embodiment, the gelling agent is carrageenan.

Carrageenan generally includes three types, iota (?), kappa (?) and lambda (?) with ?-carrageenan being preferred due to its high gel strength.

Suitable co-gelling agents to promote the gelation of gelling agent include water-soluble compounds containing one or more of potassium, ammonium, sodium and calcium ions, for example, potassium chloride, potassium phosphate, potassium acetate, calcium chloride, sodium citrate and ammonium chloride. Generally, a calcium ion is used for ?-carrageenan and a potassium ion is used for ?-carrageenan.
In a preferred embodiment, the co-gelling agent is potassium chloride or potassium acetate.

EXAMPLES
The scope of the invention can be understood better by referring to the examples given below, the aim of which is to explain the advantages of the invention. Unless otherwise specified, all parts and percentages are by weight.
Example 1:
2 kg of HPMC powder was dissolved in 7.5 kg of acidified distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20 oC to ensure complete dissolution of HPMC. To this solution added 20 g of Silicon Dioxide (SiO2) and 10 g of Titanium Dioxide (TiO2) and further stirred for 30 minutes. Further the pH of the solution was adjusted to 3.5 - 4.5 by adding required 0.1M HCl and further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients. Thus, prepared HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 25 °C. Then, performed the dip molding process by following a process similar to for the production of size # 0 HPMC capsules by thermo-gelling method. The capsules produced were pure white hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Example 2:
2.5 kg of HPMC powder was dissolved in 9.4 kg of acidified distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. To this solution added 25 g of Silicon Dioxide (SiO2) and 25 g of Titanium Dioxide (TiO2) and further stirred for 30 minutes. Further the pH of the solution was adjusted to 3.5 - 4.5 by adding required 0.1M HCl and further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients. Thus, prepared HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 25 °C. Then, performed the dip molding process by following a process similar to for the production of size # 0 HPMC capsules by thermo-gelling method. The capsules produced were pure white hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Example 3:
3 kg of HPMC powder was dissolved in 11.25 kg of acidified distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. To this solution added 30 g of Silicon Dioxide (SiO2) and 45 g of Titanium Dioxide (TiO2) and further stirred for 30 minutes. Further the pH of the solution was adjusted to 3.5 - 4.5 by adding required 0.1M HCl and further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients. Thus, prepared HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 25°C. Then, performed the dip molding process by following a process similar to for the production of size # 0 HPMC capsules by thermo-gelling method. The capsules produced were pure white hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Example 4:
30 kg of HPMC powder was dissolved in 113 kg of acidified distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. To this solution added 300 g Silicon dioxide powder and 300 g of Titanium Dioxide (TiO2) and additionally stirred for 30 minutes. Further the pH of the solution was adjusted to 3.5 -4.5 by adding required 0.1M HCl and further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients. Thus, prepared HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 25 °C. Then, performed the dip molding process by following a process similar to for the production of size # 0 HPMC capsules by thermo-gelling method. The capsules produced were pure white capsules with same dimensional specifications to the conventional hard HPMC capsules

Example 5:
2 kg of HPMC powder was dissolved in 7.5 kg of distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. To this solution added 20 g of Silicon Dioxide (SiO2) and 20 g of Titanium Dioxide (TiO2) and further stirred for 30 minutes. Thus, prepared HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 25 °C. Then, performed the dip molding process by following a process similar to for the production of size # 0 HPMC capsules by thermo-gelling method. The capsules produced were pure white hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Extra transparent capsules:

Example 6:
2 kg of HPMC powder was dissolved in 7.5 kg of acidified distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. To this solution added 20 g of Silicon Dioxide (SiO2) and further stirred for 30 minutes. Further the pH of the solution was adjusted to 3.5 -4.5 by adding required 0.1M HCl and further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients. Thus, prepared HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 25°C. Then, performed the dip molding process by following a process similar to for the production of size # 0 HPMC capsules by thermo-gelling method. The capsules produced were extra transparent hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Example 7:
30 kg of HPMC powder was dissolved in 113 kg of acidified distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. To this solution added 300 g Silicon dioxide powder and additionally stirred for 30 minutes. Further the pH of the solution was adjusted to 3.5 - 4.5 by adding required 0.1M HCl and further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients. Thus, prepared HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 25 °C. Then, performed the dip molding process by following a process similar to for the production of size # 0 HPMC capsules by thermo-gelling method. The capsules produced were extra transparent capsules with same dimensional specifications to the conventional hard HPMC capsules.
Example 8:
2 kg of HPMC powder was dissolved in 7.5 kg of distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. To this solution added 20 g of Silicon Dioxide (SiO2) and further stirred for 30 minutes. Thus, prepared HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 25°C. Then, performed the dip molding process by following a process similar to for the production of size # 0 HPMC capsules by thermo-gelling method. The capsules produced were extra transparent hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Capsules with gelling agents:
Example 9:
2 kg of HPMC powder was dispersed in 7.5 L of acidified distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. Further the pH of the solution was adjusted to 3.5 - 4.5 by adding required quantity of 0.1M HCl. Thus, obtained mixture was further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients, further the solution was kept undisturbed at room temperature for 12 hours. Thus, obtained solution was free of bubbles and clear, then increased the temperature of solution to 44°C, to this solution slowly added 8 g of potassium chloride, then slowly added previously prepared carrageenan solution (20 g carrageenan). Thus, obtained HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 44 °C. Then, performed the dip molding process by following a process similar to for the production of size # 0 conventional HPMC capsules. The capsules produced were transparent hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Example 10:
2 kg of HPMC powder was dissolved in 7.5 L of acidified distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. Further the pH of the solution was adjusted to 3.5-4.5 by adding required quantity of 0.1M HCl. Thus, obtained mixture was further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients, further solution was clear in room temperature for 12 hours. Thus, obtained mixture was further mechanically stirred for 30 minutes at 70oC to ensure uniform mixing of the ingredients, further the solution was kept undisturbed at room temperature for 12 hours. Thus, obtained solution was free of bubbles and clear, then increased the temperature of solution to 44°C and subsequently added potassium chloride (8 g) and titanium dioxide (20 g) and stirred well, and added previously prepared carrageenan solution (20 g carrageenan). Thus, obtained HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 44 °C. Then, performed the dip molding process by following a process similar to for the production of size # 0 conventional HPMC capsules. The capsules produced were transparent hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Example 11:
2 kg of HPMC powder was dispersed in 7.5 L of distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. Thus, obtained mixture was further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients, further the solution was kept undisturbed at room temperature for 12 hours. Thus, obtained solution was free of bubbles and clear, then increased the temperature of solution to 44°C, to this solution slowly added 8 g of potassium chloride, then slowly added previously prepared carrageenan solution (20 g carrageenan). Thus, obtained HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 44 °C. Then, performed the dip molding process by following a process similar to for the production of size # 0 conventional HPMC capsules. The capsules produced were transparent hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Example 12:
2 kg of HPMC powder was dissolved in 7.5 L of distilled water by heating at 80oC for 1h under constant mechanical stirring and cooled to below 20oC to ensure complete dissolution of HPMC. Thus, obtained mixture was further mechanically stirred for 30 minutes to ensure uniform mixing of the ingredients, further the solution was kept undisturbed at room temperature for 12 hours. Thus, obtained solution was free of bubbles and clear, then increased the temperature of solution to 44°C and subsequently added potassium chloride (8 g) and titanium dioxide (20 g) and stirred well, and added previously prepared carrageenan solution (20 g carrageenan). Thus, obtained HPMC solution was defoamed under slow stirring for 1 h and subsequently poured into a dipping dish of a pilot capsule manufacturing machine while keeping the dipping solution at 44 °C. Then, performed the dip molding process by following a process similar to for the production of size # 0 conventional HPMC capsules. The capsules produced were transparent hard HPMC capsules with same dimensional specifications to the conventional hard HPMC capsules.

Capsules Evaluation methods
1- Evaluation of Clarity –Suitable scale between 1 to 10 was developed where 1 is yellow and dirty and 10 is clear and water like colour. A qualitative scale of 1 to 10 is used for defining the Clarity of the capsules under evaluation.
2- Evaluation of whiteness - Suitable scale between 1 to 10 was developed where 1 is yellow opaque/ dirty and 10 is bright white. A qualitative scale of 1 to 10 is used for defining the whiteness / brightness of the capsules under evaluation.
Observation tables
Capsules produced by thermo-gelling method:
Example HPMC
(in wt %) pH TiO2
(in wt %) Clarity number Whiteness number
1 18.2 3.90 0.5 - 8
2 18.5 3.85 1 - 8
3 18.3 4.15 1.5 - 9
4 18.1 3.95 1 - 9
5 18.4 7.22 2 - 2
6 18.2 4.20 0 8 -
7 18.6 4.35 0 9 -
8 18.1 7.51 0 3 -

Capsules produced by cold-gelling method:
Example HPMC
(in wt %) Carrageenan (in wt %) pH TiO2
(in wt %) Clarity number Whiteness number
9 18.6 1.0 4.25 - 9 -
10 18.8 1.1 4.15 1 - 8
11 18.4 0.95 7.51 - 3 -
12 18.5 1.05 7.55 1 - 2

The above clearly shows that the process of the invention enhances the clarity and whiteness in HPMC capsules by thermo-gelling method and cold-gelling method.