1. Compoundin g Dr. Muslim Suardi, MSi., Apt. Faculty of Pharmacy University of Andalas Capsules

2. Capsules “Capsules are gelatin shells filled with the ingredients that make up an individual dose” Dry powders, semi-solids, & liquids that do not dissolve gelatin may be encapsulated. Dry powders, semi-solids, & liquids that do not dissolve gelatin may be encapsulated. ±20% of all prescriptions dispensed in capsules ±20% of all prescriptions dispensed in capsules

3. Advantages May be used to mask the unpleasant tastes, aromas, or appearance of a drug. May be used to mask the unpleasant tastes, aromas, or appearance of a drug. Allow powders to be dispensed in an uncompressed form, thus allowing for quicker dissolution & absorption of the drug following oral dosing (as compared with tablets). Allow powders to be dispensed in an uncompressed form, thus allowing for quicker dissolution & absorption of the drug following oral dosing (as compared with tablets).

4. Advantages Administration routes: oral, inhalation, rectal, or to be diluted for vaginal, rectal, oral or topical use. Administration routes: oral, inhalation, rectal, or to be diluted for vaginal, rectal, oral or topical use. Easier than tablets for some people to swallow. Easier than tablets for some people to swallow. Can be make to alter the release rate of the drug. Can be make to alter the release rate of the drug.

5. Disadvantages Easily tampered with (although techniques exist for preventing this). Easily tampered with (although techniques exist for preventing this). They are subject to the effects of RH & to microbial contamination. They are subject to the effects of RH & to microbial contamination. Difficult for some people to swallow. Difficult for some people to swallow. More expensive (commercially). More expensive (commercially).

6. Hard Gelatin Capsules Consists of a base or body & a shorter cap, which fits firmly over the base of the capsule. Consists of a base or body & a shorter cap, which fits firmly over the base of the capsule. For human use, eight sizes of capsules are available. The capacity of each size varies according to the combination of drugs and their apparent densities. For human use, eight sizes of capsules are available. The capacity of each size varies according to the combination of drugs and their apparent densities.

7. Hard Gelatin Capsules Available as clear gelatin capsules or in a variety of colors. Available as clear gelatin capsules or in a variety of colors. Different colored capsules to distinguish 2 capsule formulations for the same patient, or to encapsulate unattractive ingredients. Different colored capsules to distinguish 2 capsule formulations for the same patient, or to encapsulate unattractive ingredients. A dye can be added to the powder before filling a clear capsule to impart a color for identification or esthetics. A dye can be added to the powder before filling a clear capsule to impart a color for identification or esthetics.

8. Some types of hard gelatin capsules have a locking cap, which makes it more difficult to reopen the capsule Some types of hard gelatin capsules have a locking cap, which makes it more difficult to reopen the capsule

9. Relative Sizes & Capacities of Capsules Capsule Size Volume (ml)Lactose (mg)Acetosal (mg) 0001.3713401000 000.95929600 00.68665500 10.50489300 20.37362250 30.30293200 40.20195125 50.1312760

10. "Punch" Method of Compounding Capsules Punch method to hand fill capsules at the prescription counter Punch method to hand fill capsules at the prescription counter The ingredients are triturated to the same particle size & then mixed by geometric dilution. The ingredients are triturated to the same particle size & then mixed by geometric dilution. The powder is placed on a powder paper or ointment slab & smoothed with a spatula to a height approximately half the length of the capsule body. The powder is placed on a powder paper or ointment slab & smoothed with a spatula to a height approximately half the length of the capsule body.

11. Punch Method The base of the capsule is held vertically & the open end is repeatedly pushed or "punched" into the powder until the capsule is filled; the cap is then replaced to close the capsule. The base of the capsule is held vertically & the open end is repeatedly pushed or "punched" into the powder until the capsule is filled; the cap is then replaced to close the capsule. Each filled capsule is weighed using an empty capsule as a counterweight. Each filled capsule is weighed using an empty capsule as a counterweight.

12. Punch Method Powder is added or removed until the correct weight has been placed in the capsule. Powder is added or removed until the correct weight has been placed in the capsule. The filled capsule is tapped so that no air spaces are visible within the contents. The filled capsule is tapped so that no air spaces are visible within the contents.

13. Capsule Machines Available for filling 50, 100, & 300 cap at a time. Available for filling 50, 100, & 300 cap at a time. Each manufacturer's machine is slightly different in its operation, but the series of operations is the same. Each manufacturer's machine is slightly different in its operation, but the series of operations is the same. Cap are first loaded into the machine. Cap are first loaded into the machine. Most machines come with a capsule loader which correctly aligns all of the capsules in the machine base. Most machines come with a capsule loader which correctly aligns all of the capsules in the machine base.

14. Capsule Machines There are plates on the machine base that can be adjusted. There are plates on the machine base that can be adjusted. First, the plates are adjusted to hold the capsule bodies in place while the caps are removed all at one time. First, the plates are adjusted to hold the capsule bodies in place while the caps are removed all at one time. The caps remain in place in the top of the machine for later use. The caps remain in place in the top of the machine for later use.

15. Capsule Machines Then the plates are adjusted again so that the capsule bodies will "drop" into place so that the tops are flush with the working surface of the plate Then the plates are adjusted again so that the capsule bodies will "drop" into place so that the tops are flush with the working surface of the plate There are plates on the machine base that can be adjusted. First, the plates are adjusted to hold the capsule bodies in place while the caps are removed all at one time. There are plates on the machine base that can be adjusted. First, the plates are adjusted to hold the capsule bodies in place while the caps are removed all at one time.

16. Capsule Machines The caps remain in place in the top of the machine for later use. Then the plates are adjusted again so that the capsule bodies will "drop" into place so that the tops are flush with the working surface of the plate The caps remain in place in the top of the machine for later use. Then the plates are adjusted again so that the capsule bodies will "drop" into place so that the tops are flush with the working surface of the plate

17. Capsule Machines The formulation powder is poured onto the plate and special spreaders and combs are used to fill the individual capsules. Some manufacturer's have special shakers that will also help spread the powder and fill the capsules. The powder is spread evenly over the plate, and the comb is used to tamp and pack the powder into the capsules. The formulation powder is poured onto the plate and special spreaders and combs are used to fill the individual capsules. Some manufacturer's have special shakers that will also help spread the powder and fill the capsules. The powder is spread evenly over the plate, and the comb is used to tamp and pack the powder into the capsules.

18. Capsule Machines These two processes are repeated over and over again until the capsule bodies are filled with the powder. All of the caps are then simultaneously returned to the capsule bodies, and the closed capsules are removed from the machine. These two processes are repeated over and over again until the capsule bodies are filled with the powder. All of the caps are then simultaneously returned to the capsule bodies, and the closed capsules are removed from the machine.

19. Capsule Machines The machine has the advantage of filling many capsules in a timely manner. However, there is a tendency to pack the capsules in the middle of the plate with more powder than the capsules along the periphery. It takes practice to ensure that each capsule has the same amount of drug. A quality control procedure should be executed with each batch of capsules produced with the machine The machine has the advantage of filling many capsules in a timely manner. However, there is a tendency to pack the capsules in the middle of the plate with more powder than the capsules along the periphery. It takes practice to ensure that each capsule has the same amount of drug. A quality control procedure should be executed with each batch of capsules produced with the machine

20. Final Processing Once the capsules have been compounded and the capsule closed, the pharmacist may want to "seal" the capsule. Once the capsules have been compounded and the capsule closed, the pharmacist may want to "seal" the capsule. The best way is to use "locking" capsules, where the body and cap lock together, making it very difficult to open the capsule again. The best way is to use "locking" capsules, where the body and cap lock together, making it very difficult to open the capsule again.

21. Final Processing If using locking capsules, during the filling process the cap is not completely closed onto the body in the weighing procedure to determine the weight of powder in the capsule. The locking is done only one time and that is after the capsule is correctly filled If using locking capsules, during the filling process the cap is not completely closed onto the body in the weighing procedure to determine the weight of powder in the capsule. The locking is done only one time and that is after the capsule is correctly filled

22. Final Processing If locking capsules are not used, a seal can be made by touching the outer edge of the body with a moist towel to soften the gelatin. Alternatively, a cotton swab dipped in warm water can be rubbed around the inner edge of the cap. When the cap is closed on the body, it is slightly twisted to form the seal If locking capsules are not used, a seal can be made by touching the outer edge of the body with a moist towel to soften the gelatin. Alternatively, a cotton swab dipped in warm water can be rubbed around the inner edge of the cap. When the cap is closed on the body, it is slightly twisted to form the seal

23. Final Processing When compounding and sealing are complete, the capsules may need cleaning to remove fingerprints, traces of body oils, or loss powder from the capsule. Fingerprints and oils cannot be effectively cleaned from capsules so the best way to prevent these problems is to wear gloves during the compounding process. Any clinging powder can be removed by rolling the capsules between the folds of a towel When compounding and sealing are complete, the capsules may need cleaning to remove fingerprints, traces of body oils, or loss powder from the capsule. Fingerprints and oils cannot be effectively cleaned from capsules so the best way to prevent these problems is to wear gloves during the compounding process. Any clinging powder can be removed by rolling the capsules between the folds of a towel

24. Final Processing Another proposed cleaning method is to put the capsules in a container filled with sodium bicarbonate, sugar, or sodium chloride, and gently roll the container. Then the container contents can be poured into a ten-mesh sieve where the "cleaning salt" will pass through the sieve. Another proposed cleaning method is to put the capsules in a container filled with sodium bicarbonate, sugar, or sodium chloride, and gently roll the container. Then the container contents can be poured into a ten-mesh sieve where the "cleaning salt" will pass through the sieve.

25. Final Processing Capsules should be visually inspected and checked for: Capsules should be visually inspected and checked for: Uniformity - check capsules for uniformity in appearance and color. Uniformity - check capsules for uniformity in appearance and color. extent of fill - check capsules for uniformity of extent of fill to ensure that all capsules have been filled. extent of fill - check capsules for uniformity of extent of fill to ensure that all capsules have been filled. locked - check capsules to ensure that they have all been tightly closed and locked locked - check capsules to ensure that they have all been tightly closed and locked

26. Quality Control USP requires that the capsule, "shall not be less than 90% & not more than 110% of the theoretically calculated weight of each unit. USP requires that the capsule, "shall not be less than 90% & not more than 110% of the theoretically calculated weight of each unit. It is possible to have capsules that pass the weight variation requirement but not have content uniformity. It is possible to have capsules that pass the weight variation requirement but not have content uniformity.

27. Quality Control Content uniformity test: measures the variability in the amount of active drug contained in each capsule. Content uniformity test: measures the variability in the amount of active drug contained in each capsule. It is possible to have capsules that pass the weight variation requirement but not have content uniformity. This can occur if the material put into the capsules is not a homogenous mixture of all the ingredients It is possible to have capsules that pass the weight variation requirement but not have content uniformity. This can occur if the material put into the capsules is not a homogenous mixture of all the ingredients

28. Quality Control Some caps would then have more active drug than other caps. Some caps would then have more active drug than other caps. Appropriate mixing: geometric dilution of all caps ingredients into a homo- genous mixture before filling the caps. Appropriate mixing: geometric dilution of all caps ingredients into a homo- genous mixture before filling the caps. The weight variation data will be sufficient to ensure the quality of the caps. The weight variation data will be sufficient to ensure the quality of the caps.

29. Additional Considerations Caps are made of gelatin, sugar, & water & contain ±10-15% moisture. Caps are made of gelatin, sugar, & water & contain ±10-15% moisture. Gelatin can absorb up to 10x its weight in water. Gelatin can absorb up to 10x its weight in water. So if gelatin caps are placed in areas of high humidity, they will become malformed or misshapened as they absorb moisture. So if gelatin caps are placed in areas of high humidity, they will become malformed or misshapened as they absorb moisture.

30. Additional Considerations If caps are placed in low RH, they become dry & brittle & may crack. If caps are placed in low RH, they become dry & brittle & may crack. To protect caps from the extremes of RH, they should be dispensed in plastic or glass vials & stored in a cool, drug place. To protect caps from the extremes of RH, they should be dispensed in plastic or glass vials & stored in a cool, drug place. It appears that a storage RH of 30- 45% is best. It appears that a storage RH of 30- 45% is best. Cotton can be placed in the top of the vial to keep the caps from rattling. Cotton can be placed in the top of the vial to keep the caps from rattling.

31. Additional Considerations If powders that are being mixed before encapsulation are very light and fluffy and "difficult to manage," add a few drops of alcohol, water, or mineral oil. As an alternative, mix these powders in a plastic bag. If the powders seem to have a "static charge," use about 1% sodium lauryl sulfate. If powders that are being mixed before encapsulation are very light and fluffy and "difficult to manage," add a few drops of alcohol, water, or mineral oil. As an alternative, mix these powders in a plastic bag. If the powders seem to have a "static charge," use about 1% sodium lauryl sulfate.

32. Additional Considerations Mg stearate <1% can be added to powders to increase their "flowability" which makes filling caps easier. Mg stearate <1% can be added to powders to increase their "flowability" which makes filling caps easier. Mg stearate is a hydrophobic compound & may interfere with the dissolution of the powders Mg stearate is a hydrophobic compound & may interfere with the dissolution of the powders

33. Controlled Release Caps HPMC, or Methocel, is a cellulose derivative polymer that is used as a hydrophilic matrix material. HPMC, or Methocel, is a cellulose derivative polymer that is used as a hydrophilic matrix material. When Methocel hydrates, it forms a gel of such consistency that drug diffusion through the gel can be controlled. When Methocel hydrates, it forms a gel of such consistency that drug diffusion through the gel can be controlled.

34. Controlled Release Caps A hydrophilic matrix controlled release system is a dynamic system composed of polymer wetting, polymer hydration, & polymer dissolution. A hydrophilic matrix controlled release system is a dynamic system composed of polymer wetting, polymer hydration, & polymer dissolution. At the same time, other soluble excipients or drugs will also wet, dissolve, & diffuse out of the matrix while insoluble materials will be held in place until the surrounding polymer erodes or dissolves away At the same time, other soluble excipients or drugs will also wet, dissolve, & diffuse out of the matrix while insoluble materials will be held in place until the surrounding polymer erodes or dissolves away

35. Controlled Release Caps Initially, the surface becomes wet & Methocel polymer starts to partially hydrate forming a gel layer on the surface of the capsule. Initially, the surface becomes wet & Methocel polymer starts to partially hydrate forming a gel layer on the surface of the capsule. As water continues to permeate into the caps, the gel layer becomes thicker, & soluble drug will diffuse out through the gel layer. As water continues to permeate into the caps, the gel layer becomes thicker, & soluble drug will diffuse out through the gel layer.

36. Controlled Release Caps Ultimately, water will dissolve the caps shell & continue to penetrate into the drug core. So release is controlled by the dissolution of soluble drug into the penetrating water & diffusion across the gel layer Ultimately, water will dissolve the caps shell & continue to penetrate into the drug core. So release is controlled by the dissolution of soluble drug into the penetrating water & diffusion across the gel layer

37. Controlled Release Caps To formulate a successful hydrophilic matrix system, the polymer substance must wet & hydrate to form a gel layer fast enough to protect the interior of the caps from dissolving & disintegrating during the initial wetting & hydration phase. If the polymer is too slow to hydrate, gastric fluids may penetrate to the caps core, dissolve the drug substance, & allow the drug to diffuse out prematurely. To formulate a successful hydrophilic matrix system, the polymer substance must wet & hydrate to form a gel layer fast enough to protect the interior of the caps from dissolving & disintegrating during the initial wetting & hydration phase. If the polymer is too slow to hydrate, gastric fluids may penetrate to the caps core, dissolve the drug substance, & allow the drug to diffuse out prematurely.

38. Controlled Release Caps Even among the family of HPMC products (Methocel E, F, & K), there are significant differences in the rate at which the polymers will hydrate. This is due to the varying proportions of the 2 chemical substituents attached to the cellulose backbone, HPC & methoxyl substitution Even among the family of HPMC products (Methocel E, F, & K), there are significant differences in the rate at which the polymers will hydrate. This is due to the varying proportions of the 2 chemical substituents attached to the cellulose backbone, HPC & methoxyl substitution

39. Controlled Release Caps Even among the family of HPMC products (Methocel E, F, & K), there are significant differences in the rate at which the polymers will hydrate. This is due to the varying proportions of the 2 chemical substituents attached to the cellulose backbone, hydroxypropoxyl and methoxyl substitution Even among the family of HPMC products (Methocel E, F, & K), there are significant differences in the rate at which the polymers will hydrate. This is due to the varying proportions of the 2 chemical substituents attached to the cellulose backbone, hydroxypropoxyl and methoxyl substitution

40. Controlled Release Caps The methoxyl substituent is a relatively hydrophobic component & not contribute as greatly to the hydrophilic nature of the polymer & the rate at which it will hydrate. The methoxyl substituent is a relatively hydrophobic component & not contribute as greatly to the hydrophilic nature of the polymer & the rate at which it will hydrate. The hydroxpropoxyl group does contribute greatly to the rate of polymer hydration. The hydroxpropoxyl group does contribute greatly to the rate of polymer hydration.

41. Controlled Release Caps As a result, Methocel K products are the fastest to hydrate because they have the lower amount of the hydrophobic methoxyl substitution & a higher amount of the hydrophilic hydroxypropoxyl substitution. As a result, Methocel K products are the fastest to hydrate because they have the lower amount of the hydrophobic methoxyl substitution & a higher amount of the hydrophilic hydroxypropoxyl substitution. The range of chemical substitution in Methocel products is shown below. The range of chemical substitution in Methocel products is shown below.

42. Chemical Substitution in Methocel Products% Methoxyl% HydroxypropoxylRelative Rate of Hydration Methocel K19-247-12Fastest Methocel E28-307-12Next Fastest Methocel F27-304-7.5Slow Methocel A27.5-31.50Slowest

43. Controlled Release Caps Increasing the conc of the polymer in a matrix system increases the viscosity of the gel that forms on the caps surface. Increasing the conc of the polymer in a matrix system increases the viscosity of the gel that forms on the caps surface. An increase in the conc of the polymer used will generally yield a decrease in drug diffusion & drug release. An increase in the conc of the polymer used will generally yield a decrease in drug diffusion & drug release. An increase in the conc of polymer also tends to put more polymer on the caps surface. Wetting is more readily achieved so gel formation is accelerated An increase in the conc of polymer also tends to put more polymer on the caps surface. Wetting is more readily achieved so gel formation is accelerated

44. Measuring Drug Release This sample experiment was conducted in water & showed that after 2.5h, release was still continuing from the controlled release caps This sample experiment was conducted in water & showed that after 2.5h, release was still continuing from the controlled release caps

45. Rate of Release Determined by plotting the Cumulative Amount Released vs some function of time. Determined by plotting the Cumulative Amount Released vs some function of time. For matrix diffusion controlled release, adaptations of the Higuchi eq are used; time is expressed as the square root of time & has units of min 1/2. A linear trendline is fit through the points that occur after a lag time or before any asymptotic values are reached. For matrix diffusion controlled release, adaptations of the Higuchi eq are used; time is expressed as the square root of time & has units of min 1/2. A linear trendline is fit through the points that occur after a lag time or before any asymptotic values are reached.

46. Rate of Release Release of salicylic acid in 0.01N HCl is shown in the plot below. Release of salicylic acid in 0.01N HCl is shown in the plot below. Conventional caps apparently released all of its contents by 30min, since after that time the amount released remained constant. Conventional caps apparently released all of its contents by 30min, since after that time the amount released remained constant. Release rate was 1.55 mg/min 1/2 which is almost 3x as fast as seen with the controlled release caps Release rate was 1.55 mg/min 1/2 which is almost 3x as fast as seen with the controlled release caps

47. Rate of Release But more importantly, the controlled release caps continuously releases drug for hours, where the conventional capsule released all the drug within 30min But more importantly, the controlled release caps continuously releases drug for hours, where the conventional capsule released all the drug within 30min