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

CompoundCompoundinging

Dr. Muslim Suardi, MSi., Apt. Dr. Muslim Suardi, MSi., Apt. Faculty of Pharmacy University of Faculty of Pharmacy University of

AndalasAndalas

Capsules

CapsulesCapsules

““Capsules are gelatin shells filled Capsules are gelatin shells filled with the ingredients that make up with the ingredients that make up

an individual dose”an individual dose” Dry powders, semi-solids, & Dry powders, semi-solids, &

liquids that do not dissolve gelatin liquids that do not dissolve gelatin may be encapsulated. may be encapsulated.

±20% of all prescriptions ±20% of all prescriptions dispensed in capsules dispensed in capsules

AdvantagesAdvantages

May be used to mask the unpleasant May be used to mask the unpleasant tastes, aromas, or appearance of a tastes, aromas, or appearance of a drug.drug.

Allow powders to be dispensed in an Allow powders to be dispensed in an uncompressed form, thus allowing uncompressed form, thus allowing for quicker dissolution & absorption for quicker dissolution & absorption of the drug following oral dosing (as of the drug following oral dosing (as compared with tablets).compared with tablets).

AdvantagesAdvantages

Administration routes: oral, Administration routes: oral, inhalation, rectal, or to be diluted inhalation, rectal, or to be diluted for vaginal, rectal, oral or topical for vaginal, rectal, oral or topical use.use.

Easier than tablets for some Easier than tablets for some people to swallow.people to swallow.

Can be make to alter the release Can be make to alter the release rate of the drug.rate of the drug.

DisadvantagesDisadvantages

Easily tampered with (although Easily tampered with (although techniques exist for preventing techniques exist for preventing this).this).

They are subject to the effects of They are subject to the effects of RH & to microbial contamination.RH & to microbial contamination.

Difficult for some people to Difficult for some people to swallow.swallow.

More expensive (commercially).More expensive (commercially).

Hard Gelatin CapsulesHard Gelatin Capsules

Consists of a base or body & a Consists of a base or body & a shorter cap, which fits firmly over shorter cap, which fits firmly over the base of the capsule. the base of the capsule.

For human use, eight sizes of For human use, eight sizes of capsules are available. The capsules are available. The capacity of each size varies capacity of each size varies according to the combination of according to the combination of drugs and their apparent densities. drugs and their apparent densities.

Hard Gelatin CapsulesHard Gelatin Capsules

Available as clear gelatin capsules or Available as clear gelatin capsules or in a variety of colors. in a variety of colors.

Different colored capsules to Different colored capsules to distinguish 2 capsule formulations for distinguish 2 capsule formulations for the same patient, or to encapsulate the same patient, or to encapsulate unattractive ingredients. unattractive ingredients.

A dye can be added to the powder A dye can be added to the powder before filling a clear capsule to impart before filling a clear capsule to impart a color for identification or esthetics.a color for identification or esthetics.

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

Relative Sizes & Relative Sizes & Capacities of Capsules Capacities of Capsules

Capsule Size

Volume (ml) Lactose (mg) Acetosal (mg)

000 1.37 1340 1000

00 0.95 929 600

0 0.68 665 500

1 0.50 489 300

2 0.37 362 250

3 0.30 293 200

4 0.20 195 125

5 0.13 127 60

"Punch" Method of "Punch" Method of Compounding Compounding

CapsulesCapsules Punch method to hand fill capsules at Punch method to hand fill capsules at

the prescription counterthe prescription counter The ingredients are triturated to the The ingredients are triturated to the

same particle size & then mixed by same particle size & then mixed by geometric dilution. geometric dilution.

The powder is placed on a powder paper The powder is placed on a powder paper or ointment slab & smoothed with a or ointment slab & smoothed with a spatula to a height approximately half spatula to a height approximately half the length of the capsule body. the length of the capsule body.

Punch MethodPunch Method

The base of the capsule is held The base of the capsule is held vertically & the open end is vertically & the open end is repeatedly pushed or "punched" into repeatedly pushed or "punched" into the powder until the capsule is filled; the powder until the capsule is filled; the cap is then replaced to close the the cap is then replaced to close the capsule. capsule.

Each filled capsule is weighed using Each filled capsule is weighed using an empty capsule as a an empty capsule as a counterweight. counterweight.

PunchPunch MethodMethod

Powder is added or removed until Powder is added or removed until the correct weight has been the correct weight has been placed in the capsule. placed in the capsule.

The filled capsule is tapped so The filled capsule is tapped so that no air spaces are visible that no air spaces are visible within the contents.within the contents.

Capsule MachinesCapsule Machines

Available for filling 50, 100, & 300 cap Available for filling 50, 100, & 300 cap at a time. at a time.

Each manufacturer's machine is slightly Each manufacturer's machine is slightly different in its operation, but the series different in its operation, but the series of operations is the same. 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 Most machines come with a capsule

loader which correctly aligns all of the loader which correctly aligns all of the capsules in the machine base. capsules in the machine base.


There are plates on the machine There are plates on the machine base that can be adjusted. base that can be adjusted.

First, the plates are adjusted to First, the plates are adjusted to hold the capsule bodies in place hold the capsule bodies in place while the caps are removed all at while the caps are removed all at one time. one time.

The caps remain in place in the The caps remain in place in the top of the machine for later use. top of the machine for later use.


Then the plates are adjusted again so Then the plates are adjusted again so that the capsule bodies will "drop" that the capsule bodies will "drop" into place so that the tops are flush into place so that the tops are flush with the working surface of the platewith the working surface of the plate

There are plates on the machine base There are plates on the machine base that can be adjusted. First, the plates that can be adjusted. First, the plates are adjusted to hold the capsule are adjusted to hold the capsule bodies in place while the caps are bodies in place while the caps are removed all at one time. removed all at one time.


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


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


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


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

Final ProcessingFinal Processing

Once the capsules have been Once the capsules have been compounded and the capsule compounded and the capsule closed, the pharmacist may want closed, the pharmacist may want to "seal" the capsule. to "seal" the capsule.

The best way is to use "locking" The best way is to use "locking" capsules, where the body and cap capsules, where the body and cap lock together, making it very lock together, making it very difficult to open the capsule again. difficult to open the capsule again.


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


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


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


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


Capsules should be visually inspected and Capsules should be visually inspected and checked for:checked for:

Uniformity - check capsules for uniformity Uniformity - check capsules for uniformity in appearance and color.in appearance and color.

extent of fill - check capsules for extent of fill - check capsules for uniformity of extent of fill to ensure that uniformity of extent of fill to ensure that all capsules have been filled.all capsules have been filled.

locked - check capsules to ensure that locked - check capsules to ensure that they have all been tightly closed and they have all been tightly closed and lockedlocked

QualityQuality ControlControl

USP requires that the capsule, USP requires that the capsule, "shall not be less than 90% & not "shall not be less than 90% & not more than 110% of the theoretically more than 110% of the theoretically calculated weight of each unit. calculated weight of each unit.

It is possible to have capsules that It is possible to have capsules that pass the weight variation pass the weight variation requirement but not have content requirement but not have content uniformity. uniformity.


Content uniformity test: measures the Content uniformity test: measures the variability in the amount of active variability in the amount of active drug contained in each capsule. drug contained in each capsule.

It is possible to have capsules that It is possible to have capsules that pass the weight variation requirement pass the weight variation requirement but not have content uniformity. This but not have content uniformity. This can occur if the material put into the can occur if the material put into the capsules is not a homogenous capsules is not a homogenous mixture of all the ingredientsmixture of all the ingredients


Some caps would then have more Some caps would then have more active drug than other caps. active drug than other caps.

Appropriate mixing: geometric Appropriate mixing: geometric dilution of all caps ingredients into a dilution of all caps ingredients into a homogenous mixture before filling homogenous mixture before filling the caps. the caps.

The weight variation data will be The weight variation data will be sufficient to ensure the quality of the sufficient to ensure the quality of the caps.caps.

AdditionalAdditional ConsiderationsConsiderations

Caps are made of gelatin, sugar, & Caps are made of gelatin, sugar, & water & contain ±10-15% moisture. water & contain ±10-15% moisture.

Gelatin can absorb up to 10x its Gelatin can absorb up to 10x its weight in water. weight in water.

So if gelatin caps are placed in So if gelatin caps are placed in areas of high humidity, they will areas of high humidity, they will become malformed or misshapened become malformed or misshapened as they absorb moisture. as they absorb moisture.


If caps are placed in low RH, they If caps are placed in low RH, they become dry & brittle & may crack. become dry & brittle & may crack.

To protect caps from the extremes of RH, To protect caps from the extremes of RH, they should be dispensed in plastic or they should be dispensed in plastic or glass vials & stored in a cool, drug place. glass vials & stored in a cool, drug place.

It appears that a storage RH of 30-45% is It appears that a storage RH of 30-45% is best. best.

Cotton can be placed in the top of the Cotton can be placed in the top of the vial to keep the caps from rattling.vial to keep the caps from rattling.


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


Mg stearate <1% can be added to Mg stearate <1% can be added to powders to increase their powders to increase their "flowability" which makes filling "flowability" which makes filling caps easier. caps easier.

Mg stearate is a hydrophobic Mg stearate is a hydrophobic compound & may interfere with compound & may interfere with the dissolution of the powdersthe dissolution of the powders

Controlled Release Controlled Release CapsCaps

HPMC, or Methocel, is a cellulose HPMC, or Methocel, is a cellulose derivative polymer that is used as derivative polymer that is used as a hydrophilic matrix material. a hydrophilic matrix material.

When Methocel hydrates, it forms When Methocel hydrates, it forms a gel of such consistency that a gel of such consistency that drug diffusion through the gel can drug diffusion through the gel can be controlled. be controlled.


A hydrophilic matrix controlled release A hydrophilic matrix controlled release system is a dynamic system composed system is a dynamic system composed of polymer wetting, polymer hydration, & of polymer wetting, polymer hydration, & polymer dissolution. polymer dissolution.

At the same time, other soluble At the same time, other soluble excipients or drugs will also wet, excipients or drugs will also wet, dissolve, & diffuse out of the matrix while dissolve, & diffuse out of the matrix while insoluble materials will be held in place insoluble materials will be held in place until the surrounding polymer erodes or until the surrounding polymer erodes or dissolves awaydissolves away


Initially, the surface becomes wet & Initially, the surface becomes wet & Methocel polymer starts to partially Methocel polymer starts to partially hydrate forming a gel layer on the hydrate forming a gel layer on the surface of the capsule. surface of the capsule.

As water continues to permeate into As water continues to permeate into the caps, the gel layer becomes the caps, the gel layer becomes thicker, & soluble drug will diffuse thicker, & soluble drug will diffuse out through the gel layer. out through the gel layer.


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


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


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


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


The methoxyl substituent is a The methoxyl substituent is a relatively hydrophobic component relatively hydrophobic component & not contribute as greatly to the & not contribute as greatly to the hydrophilic nature of the polymer hydrophilic nature of the polymer & the rate at which it will hydrate.& the rate at which it will hydrate.

The hydroxpropoxyl group does The hydroxpropoxyl group does contribute greatly to the rate of contribute greatly to the rate of polymer hydration.polymer hydration.


As a result, Methocel K products are As a result, Methocel K products are the fastest to hydrate because they the fastest to hydrate because they have the lower amount of the have the lower amount of the hydrophobic methoxyl substitution & hydrophobic methoxyl substitution & a higher amount of the hydrophilic a higher amount of the hydrophilic hydroxypropoxyl substitution. hydroxypropoxyl substitution.

The range of chemical substitution in The range of chemical substitution in Methocel products is shown below.Methocel products is shown below.

Chemical Substitution Chemical Substitution in Methocelin Methocel

Products % Methoxyl % Hydroxypropoxyl Relative Rate of Hydration

Methocel K 19-24 7-12 Fastest

Methocel E 28-30 7-12 Next Fastest

Methocel F 27-30 4-7.5 Slow

Methocel A 27.5-31.5 0 Slowest


Increasing the conc of the polymer in a Increasing the conc of the polymer in a matrix system increases the viscosity of matrix system increases the viscosity of the gel that forms on the caps surface.the gel that forms on the caps surface.

An increase in the conc of the polymer An increase in the conc of the polymer used will generally yield a decrease in drug used will generally yield a decrease in drug diffusion & drug release. diffusion & drug release.

An increase in the conc of polymer also An increase in the conc of polymer also tends to put more polymer on the caps tends to put more polymer on the caps surface. Wetting is more readily achieved surface. Wetting is more readily achieved so gel formation is acceleratedso gel formation is accelerated

Measuring Drug Measuring Drug ReleaseRelease

This sample experiment was This sample experiment was conducted in water & showed that conducted in water & showed that after 2.5h, release was still after 2.5h, release was still continuing from the controlled continuing from the controlled release capsrelease caps

Rate of ReleaseRate of Release

Determined by plotting the Cumulative Determined by plotting the Cumulative Amount Released vs some function of Amount Released vs some function of time. time.

For matrix diffusion controlled release, For matrix diffusion controlled release, adaptations of the Higuchi eq are used; adaptations of the Higuchi eq are used; time is expressed as the square root of time is expressed as the square root of time & has units of mintime & has units of min1/21/2. A linear . A linear trendline is fit through the points that trendline is fit through the points that occur after a lag time or before any occur after a lag time or before any asymptotic values are reached. asymptotic values are reached.


Release of salicylic acid in 0.01N HCl Release of salicylic acid in 0.01N HCl is shown in the plot below. is shown in the plot below.

Conventional caps apparently Conventional caps apparently released all of its contents by 30min, released all of its contents by 30min, since after that time the amount since after that time the amount released remained constant. released remained constant.

Release rate was 1.55 mg/minRelease rate was 1.55 mg/min1/21/2 which which is almost 3x as fast as seen with the is almost 3x as fast as seen with the controlled release caps controlled release caps


But more importantly, the But more importantly, the controlled release caps controlled release caps continuously releases drug for continuously releases drug for hours, where the conventional hours, where the conventional capsule released all the drug capsule released all the drug within 30minwithin 30min

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

Documents

capsules capsules

clear gelatin capsules

sizes of capsules

types of hard gelatin

different colored capsules

clear capsule

gelatin shells

capsule formulations