Solid Dosage Forms - Capsule - PDF

Definition: Capsules are solid dosage forms in which the medication is contained within hard or soft gelatin shell. Types of materials to be filled in capsules: 1-dry solids: powders-granules-pellets-tablets. 2-semisolids: thermo-softing materials- thixotropic materials-pastes. 3- liq...

Definition: Capsules are solid dosage forms in which the medication is contained within hard or soft gelatin shell. Types of materials to be filled in capsules: 1-dry solids: powders-granules-pellets-tablets. 2-semisolids: thermo-softing materials- thixotropic materials-pastes. 3- liquids: water-miscible liquids and water-immiscible oils. 4-Granules: which are produced by granulation and tend to be more irregular than pellets which are produced by coating or microencapsulation techniques 5-Tablets: are filled into capsules : A- to produce special release form, B- to separate incompatible ingredients or C- for compounding of potent drugs. 6-Suspension: Insoluble drugs can be dispersed. 7-Water-immiscible oils: fixed and aromatic vegetable oils aliphatic, aromatic and chlorinated hydrocarbons, and liquid ethers and esters 8-Water-miscible liquids: PEG 400 and 600, alcohols e.g. isopropyl alcohol, polyglycerol, triacetin, glyceryl esters, sorbitan ester, sugar esters and polyglyceryl esters. Propylene glycol and glycerol can be used up to 10 % only to prevent migration into gelatin and softening of the shell Limitation: 1- drugs or excipients containing high concentration of water or other gelatin solvents cannot be incorporated 2- emulsions are not recommended since they are unstable and will crack as the is lost from the shell in the manufacturing process. 3- Surfactants may have a deleterious effect on capsule shell 4- Extremes of pH must be avoided. pHs below about 2.5 attack the gelatin leading to hydrolysis and subsequent leakage and PHs above about 7.5 having a tanning effect on the gelatin 5- Aldehydes must be avoided since they have a tanning action on the proteins of the gelatin shell Advantages: 1- they mask the odor and taste of unpleasant drugs. 2- they are attractive in appearance. 3- they are easy to swallow 4- less additives are required 5- rapid release of drugs. 6- they can be colored to give protection against light. 7- give good protection against air and moisture. 8- the shell is physiologically inert. 9- complicated machines are unnecessary on small scale. 10-offer greater flexibility for physician in dosage and drug combinations. Disadvantages: 1- they are not suitable for liquids that dissolve gelatin. 2- very soluble salts such as bromides and iodides should not be dispensed in capsules. The rapid release of such medications may cause gastric irritation owing to the formation of localized area of high drug content Sizes and shapes: Human use: 8 sizes are available ranging from 000(the largest) to 5(the smallest). The largest size normally acceptable to patients is a No. 0. Storage: Capsules should be stores in tightly closed glass containers, protected from dust and extremes of humidity and temperature. Capsules generally contain from 13 to 16 % of moisture. However: when stored under condition of high humidity, sufficient moisture may be absorbed to soften the gelatin and make it tacky. On the other hand, when stored under condition of low humidity, the capsules may be dehydrate and become brittle. Preparation of shell of hard gelatin Capsule : 1. First step is make gelatin solution 30-40% : gelatin and hot demineralized water are mixed under vacuum to assist in removal of entrapped air from this viscous solution. Source of gelatin: Partial hydrolysis of collagen obtained from skin, bones and white connective tissues of animals. This long polypeptide chain yields on hydrolysis 18 amino acids, the most prevalent of which are glycine and alanine. There are two basic types of gelatin. type A acid hydrolysis of pork skin type B alkaline hydrolysis of animal bones Specifications of gelatin: A- Bloom strength( gel strength): Bloom strength is an empirical gel strength measure which gives an indication of the firmness of the gel. Bloom strengths in the range 150 to 280 g are used for capsules. Higher val for soft gelatin one B- Viscosity: The viscosity of gelatin solutions is vital to the control of the thickness of the cast film. generally in the range 30 to 60 millipoise (mP).  3. Dyes, other ingredients, and any needed water 2. After aging in are added to the stainless steel gelatin in the receiving tanks, feed tanks to the gelatin make the dipping solution is solution. The transferred to feed tanks are stainless steel then used to feed tanks. gravity-feed gelatin into the Capsule Machine. The other used ingredients are a) Colorants: Commonly used pigments are the iron oxides. Colorants not only play a role in identify the product, but may also play a role in improving patient compliance. b) Opaquing Agents: Titanium dioxide may be included to render the shell opaque. Opaque capsules may be employed to provide protection against light c) Preservatives parabens are often selected. 4- Preparation of the shell: A- Dipping: Pairs of stainless steel pins are dipped into the dipping solution, at temperature 50 oC in a heated jacketed dipping pan. The time is about 12 sec. the larger the capsule the longer the dipping time. B- Rotation: Spinning the pins to distribute the gelatin uniformly over the pins. During spinning the gel may be firmed by a blast of cold air. C- Drying The racks of gelatin-coated pins then pass into a series of four drying ovens.The drying is done by dehumidification, and the temperature is adjusted to prevent film melting. D- Stripping A series of bronze jaws strip the cap and body portions of the capsules from the pins. E- Trimming: The stripped cap and body portions are delivered to collets in which they are firmly held. As the collets rotate, knives are brought against the shells to trim them to the required length. F- Joining: The cap and body portions are aligned concentrically in channels and the two portions are slowly pushed together. 3- Sorting: The capsules passing on a lighted moving conveyor are examined visually by inspectors. Any defective capsules are removed manually. Defects are classified as follows: defects that could cause stoppage of a filling machine, such as imperfect cuts, capsules with holes. defects may cause problem on use, such as splits, long bodies, or grease inside. 4- Printing: capsules are printed prior to filling. Empty capsules can be handled faster than filled capsule. printing is done on rotary presses having throughput capabilities as high as 3/4 million capsules per hour. Preparation of hard gelatin capsules 1- Formulation. 2- Filling. 3- Cleansing and polishing. 1- Formulation and selection the suitable size. Generally additives are added for the following purposes: A- Bulking agents B- Lubricants C- Adsorbents D- Wetting agents 2- Filling: A- Small Scale: Punch method. Plastic block or suppository mold The lower halves of the capsules may be supported in the holes of suppository mold or in a plastic block. The powders are poured by a funnel in each capsule.. Hand operating device The capsules are placed manually and the caps are removed and replaced mechanically by the top plate. The powders are distributed uniformly into capsules by spreading it over a perforated tray which holds the powder over the empty body. B- Large Scale: Semiautomatic e.g. Automatic machines Elanco no.8 Lilly, Park-davis, Zanasi , Hofliger and Karg 1.Empty Capsule hopper 2.Rectifying roller 3.Cap Segment 4.Body disc 5.Powder filling hopper 6.Unopened Capsules rejection unit 7.Joining station 8.Discharge chute 9.Segment cleaning 10.Weight Control unit 11.Control station 12.Auger Motor 13.Auxiliary powder hopper Basic steps (operation) of filling machines: 1- Rectification (orientation of the empty capsules): Capsules firstly are put in capsule hopper A metal finger strikes them in the middle of rectifying roller causing them to rotate causing the body-end downward. so, capsule cap can stay in upper holding ring and capsule body can stay in lower holding ring. 2- Separation of caps from bodies: The capsules are feed into sets of holders or bushes, the diameter of which are designed so that the body can pass through the upper one but not the caps. This transfer is usually with vacuum. Separate the holding ring, put the lower (body) holding ring on the rotary table pull the powder hopper over the lower (body) holding ring, then auger inside powder hopper starts to run and fill powder into the capsule body. While Iower holding ring turns one circle, push powder hopper to its original position. 3- Dosing of fill material: Various methods are employed for powder filling, as described below. 1 - The auger: This system is principally used on semiautomatic machines. Empty capsules are fed into a pair of ringed holders where the caps are retained in one half and the bodies in the other. The bodies in their holders are passed under a powder hopper inside which a revolving auger or screw. Materials are transferred into bodies by the movement of the auger. The quantity of the powder is depend upon: The speed of revolution The design of the auger, The quantity of the powder in the hopper and The time the body is under the hopper. To obtain the best uniformity of weight it is necessary to fill the body as completely as possible. The machine is semiautomatic because: it requires a person to transfer the capsules from one operation to another; capsule feeding, filling and closing. 2- The Dosator (the most commonly used)This is used on fully automatic machines. It consists of: A dosing tube inside of which there is a spring loaded piston. The tube is plunged ,open and first, into a powder bed, in which material rises up in the tube to the piston to form a plug (slug) of powder (the powder must have some cohesive properties otherwise the powder will leave the dosator). The assembly is then raised and positioned over the capsule body. The piston is lowered ejecting the powder plug into the capsule. The fill weight can be varied by adjusting the position of the piston inside the dosing tube or altering the depth of the powder bed. Diagram of a dosator or dosing 3- The dosing disk: The dosing disk, has a number of holes bored through it. A solid brass “stop” plate slides along the bottom of the dosing disk to close off these holes Five sets of pistons (Hofliger-Karg machines) compress the powder into the cavities to form plugs. The cavities are indexed under each of the five sets of pistons so that each plug is compressed five times per cycle. After the five tamps, the dosing disk indexes to position the plugs over empty capsules bodies, where they are ejected by transfer piston. The dose is controlled by: The thickness of the dosing disk (i.e. cavity depth) the depth of the powder bed the tamping pressure. 4- Replacement of caps and ejection of filled capsules: The cap and body pushing portions are rejoined. pins are used to push the filled bodies up into the caps for closure, and to push the closed capsules out of the bushings. Compressed air also may be used to eject the capsules. 5- Locking and sealing: To prevent accidental separation of capsules during handling and shipping. Techniques: 1- Park davis kapseal : The sealing is done by a narrow band of colored gelatin. 2- Coni-snap: The rims of the body are not straight but tapered slightly. 3- Coni-snap supro: The caps extended so far over the body that only the round edges of the latter is visible. 4- Capsugel low-temperature thermal method: using a low-temperature thermal method (40 - 45° C). The capsules are first immersed for fraction of a second in a hydroalcoholic solvent. Excess solvent is then drained off, leaving traces in the overlapping area of the cap and body (held by capillary forces). Finally, the capsules are dried with warm air. Soft glatin capsules The capsules consists of units with a continous gelatin shell surrounding a liquid fill material. The capsules are formed ,filled and sealed in one operation and may be of different types and shapes. Properties Hard Gelatin Capsules Soft Gelatin Capsules 1- The Empty The basic shell is made Sugar is replaced by a plasticizer such as glycerol Shell from gelatin or sorbitol which give elasticity and softness on the wall. 5% sugar can be added to give chewable property to the shell. 2-Suitability Mainly for solids. Suitable for liquid drugs, pasty drugs, drug Liquids (except water) solutions, volatile drugs or drugs susceptible to can be added. deterioration by air (hermetically sealed). Solids can be incorporated. 3- Shell wall More thicker 4- No. of pieces Two (cap and body) One: cannot be opened without destroying the sealed together by a capsules. banding process or locked together by means of spot welding or by mechanical interlock built onto 5- Shape Cylindrical Round, oval, oblong, tube and others 6- Small scale Can be prepared It is not easily prepared except on large scale. 7- Accuracy More accurate 8-Manufacture a- The shell in one Both (a) and (b) in one operation operation b- Filling in a completely separate operation Advantages of SGC: 1- To solve the problems of compression: A- Some drugs are liquids and thus cannot be compressed into tablets. B-Low melting point drugs as piperment oils and phospholipids which melt at the temperature of compaction and cause picking and sticking problems. C- Many are dusty or cohesive and will not flow. 2- To solve the problems of mixing and powder flow: Powder flow and mixing problems may cause weight variation and dose content variation in both tablets and HGC. This can result in toxic side effects(e.g. nausea) or poor therapeutic activity in the case of potent compounds as hormones with low therapeutic index. But the pump used in SGC filling machine has very low weight variations. 3- To solve the problems of stability: Most drug compounds degraded by oxidation, hydrolysis and by incompatibility reactions during storage after manufacture because of moisture as vancomycin ( hygroscopic drug). This can be solved by the use of SGC in which the drug can be dissolved or dispersed in oil and then encapsulated in a dry shell of gelatin at low RH or under nitrogen. Such formulations resist gaseous diffusion and contain little labile water. The stability to oxidation (vitamin C) and hydrolysis (vitamin A and thiamine) is greater when the actives ingredients are formulated in SGC. 4- To solve the problems of bioavailability: Some drugs, such as neutral compounds or organic acids, are insoluble in water and GIT fluids and the dissolution rate is low. when these materials are compounded into tablets or HGC, the absorption rate is sometimes retarded and the bioavailability may be poor. In a SGC formulation the medicament is in solution or is dispersed as a fine suspension in either a hydrophilic vehicle or a hydrophobic base. When SGC is ingested, the gelatin shell dissolves and the liquid medicament is released into the gastric contents where water-miscible vehicles dissolves and oily liquids emulsify to give a drug dispersion of high surface area and good bioavailability. EX, Ibuprofen and nifedipine.  Methods of filling Rotary die method: The gelatin mass is maintained at a temperature of 57 to 60° C before and during the capsulation process. The gelatin mass is fed by gravity to a metering device (spreader box) which control the flow of the mass onto air cooled (13-14°C) rotating drum. Gelatin ribbons of controlled (± 10%) thickness are formed The ribbons are fed through a mineral oil lubricating bath, over a guide roll, and then down between the wedge and the die rolls. The material to be capsulated flows by gravity into a positive displacement pump. The pump accurately meters the material through the leads and wedge and into the gelatin ribbons between the die rolls. The capsules is about half sealed when the pressure of the pumped material forces the gelatin into the die pockets, where the capsules are simultaneously filled, shaped, hermetically sealed, and cut from the gelatin ribbon. The sealing of the capsules is achieved by mechanical pressure on the die rolls and the heating (37 to 40° C) of the ribbon by the wedge.  The filled capsules are then deposited on a conveyor which first carries them through a naphtha ( hydrocarbon distillate left over from refining wash to remove the mineral oil used to lubricate the gelatin strips ,and then to an infrared rapid drying stage where most of water is removed from the shell. Final drying to moisture content of 6-10 % is accomplished in forced air drying tunnels where the moisture content of the shell is allowed to come to equilibrium with relatively dry air (20-30 % relative humidity at 70-75 F)  Storage of SGC: Products containing hygroscopic liquids, however, should be protected against moisture and be packed in containers such as glass bottles with screw caps and waxed wad seal. For good stability the temperature should be maintained below 30 C. Evaluation of capsules 1- Disintegration BP. 1993 Introduce one tablet or capsule in each tube, add a disc to each tube. Suspend the assembly in the beaker containing the specified liquid and operate the apparatus for the specified time. Remove the assembly from the liquid. The tablets or capsules pass the test if all six have disintegrated. Disintegration: measure the breakdown of dosage form into granules Specifications: 1- 15 min. and 30 min. are the normal disintegration time for tablets and capsules respectively. 2- Water or 0.1 M HCL are liquids for HG. 3- The disc is integral part in case of SC. The disc (plastic disk with holes) is omitted in two case. A- If the preparation being examined fails to comply because of adherence to the disc. In this case the test should be repeated without it B- If the liquid ingredient supplied in SGC attack the disc. 2- Dissolution B.P. 1993 There are three types of apparatus: A- Rotating basket (apparatus I ). B- Rotating paddle (apparatus II). C- Flow through cell (apparatus III ) Dissolution measures the drug being solubilized in media (i.e) the process of dissolving solid solute in liquid solvent. The apparatus I consists of a cylindrical steel basket into which the tablet or capsule is placed, and the basket is then rotated in a bath of dissolution fluid. (the temp is maintained at 37 C ). A sample is withdrawn from the dissolution medium after a specified time (usually 45 minutes) and analyzed Not less than 70 % of the stated content should be dissolved. Five replicates are carried out and if one of these fails to reach the standard, then five more tablets or capsules are tested, and now none should fail. N.B: When capsule shell interfere with analysis, remove the contents of no fewer than six capsules as completely as possible and dissolve the empty capsule shell in the specified volume of dissolution medium and make any necessary correction. Correction factors should not be greater than 25 % of the labeled content. Specifications: 1- The dissolution fluid is chosen according to the nature of the drug substance: A- 0.1M HCl is specified for bases such as chloroquine phosphate and quinine sulfate. B- A less acid medium (pH 6.8 phosphate buffer) is specified for acidic drugs such as phenoxy methyl penicillin. C- Water is suitable for neutral molecules such as digoxin. 2- The test for SGC AS HGC if the liquid fill is hydrophilic. In case of oil fills, the test is not suitable since the oil float on the surface - Content uniformity: It is performed to ensure the proper mixing of the capsule contents by determining individually the content of 10 capsules taken randomly and determine average content. N.B. (1) According to USP, content uniformity test is done for capsules containing less than 25% of the total weight. N.B. (2) When content uniformity test is required, no need for the weight uniformity test. Limit: NMT one capsule falls outside the limit 85-115% of the average content and none outside the limit 75 - 125% of the average content. Weight Uniformity: It is done to ensure homogeneity of dosage by weighing individually 20 capsules taken randomly and determine average weight. It is done for HGC containing 25% drug or more of the total weight. Method: 1- Weigh an intact capsule. 2- Open the capsule without losing any part of the shell and remove the contents as completely as possible. 3- Weigh the shell. 4- The weight of the contents is the difference between the weighing. 5- Repeat the procedure with a further 19 capsules selected at random. 6- Determine the average weight. Limit: Not more than two of the individual weights deviate from the average weight by more than the percentage deviation shown in the table below, and none deviates by more than twice that percentage. Average weight % Deviation Less than 300 mg 10% 300 mg or more 7.5%