1. CAPSULES
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2. Raw Materials For Gelatin Capsules
Four essential basic Properties
1-Non- toxic
2-readily soluble in biological fluid at body temp.
3-It is good film forming material.
4-As a solution in water or a water –glycerol blend it undergoes a reversible phase change from a sol to gel at temp only a few degrees above ambient.
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3. Animal bones & skin are row material for manufacture.
Gelatin is of natural origin but does not occur as such in nature. It is prepared by HOH of collagen w` is the main protein constituent of connective tissues.
Animal bones & skin are row material for manufacture.
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4. Type A Type B Two main types of gelatin:
Type A by acid .Type B by basic.
Skins are acid processed whereas bones are basic processed .
Type A
Type B
Produced by acid hydrolysis.
The acid process takes about 7-10 days.
Used mainly for animal skins, because they require less pretreatment than do bones.
Produced by basic hydrolysis.
The basic process takes about 10 times as long as acid process.
Used mainly for bovine bones
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5. Gelatin Viscosity control the thickness of film or sheet.
properties of Gelatin w` are most important for capsule manufacture are Bloom strength& the Viscosity.
Bloom strength :is a measure of gel rigidity& is expressed as the load in grams required to push a standard plunger a set distance into a prepared gelatin gel (6.66% solution at 10o c).
The gelatin for hard capsule is high bloom& for soft capsule lower bloom is used ( bloom).
Gelatin Viscosity control the thickness of film or sheet.
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6. Glycerol, sorbitol , PEG ,sucrose & acacia.
Plasticizers: wall of hard gelatin cap are hard & rigid whereas wall of soft gelatin cap are more soft &flexible. The cap is soft because it contain larger proportion of Plasticizer.
Ex of Plasticizer:
Glycerol, sorbitol , PEG ,sucrose & acacia.
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7. Colorants: 2 kinds, soluble dyes synthetic origin & insol pigments.
The pigments are 2 types
1-titanium dioxide (white& is used as opacifying agent .
2-Oxides of iron ( black, red & yellow). For the manufacture of bicolored SGC aluminum lakes are used to prevent color
transfer between the two layer of the capsule.
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8. Preservatives: are sometimes added to capsules as in-process aid in order to prevent microbiological contamination during manufacture. . In the finished capsules, the moisture levels are such that the capsules will not support bacterial growth. Soft gelatin capsules sometimes have antifungal agents added to them to prevent growth on their surfaces when they are stored in non-protective packages.
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9. HARD GELATIN CAPSULES
Sizes of hard gelatin capsule shells
The hard gelatin capsule is made in a range of eight sizes from size 000, the largest, to size 5, the smallest . The most popular sizes in practice are size 0 through to 4.
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11. Manufacture into dipped
Metal moulds hot gelatin solution: gels to form
into
Dried, cut, removed from the moulds film
& two parts are joined together.
N.B. The difference today is that the operation is now fully automated as a continuous process on large machines housed in air conditioned buildings.
There are few specialist companies that manufacture empty capsule shells.
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12. Preparation of the capsule shell for hard gelatin capsules
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13. Determination of capsule fill weight
Capsule fill weight = tapped bulk density of formulation x capsule volume
Filling: Hard gelatin capsules are most frequently filled with powders
The only limitation is that they should not react with the gelatin, e.g. aldehydes, or interfere with the integrity of the shell, e.g. water which will soften the wall.
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14. Capsule filling machine
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15. I- be able to be accurately dosed into the capsule shell.
All formulations for filling into capsules must possess two basic requirements They must:
I- be able to be accurately dosed into the capsule shell.
2- release their active contents in a form which is available to the patient.
the formulation is usually a simple blend of the active ingredients with
adjutants which aid the process, e.g. diluents, glidants, lubricants and surfactants.
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16. Formulation of powders for filling
The factor which contributes most to a uniformly
filled capsule is powder flow.
powder bed from which the dose of mix is measured needs to be homogeneous, packed reproducibly, in order to give uniform fill weights.
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17. Good packing is assisted by good powder flow and this is aided by mechanical devices on the filling machine. Low dose drugs can be made to flow well by mixing with free flowing diluents, e.g. maize starch. For higher dose drugs the space available within the capsule shell far formulation aids is minimal. Small quantities (up to about 5% w/w) of highly active materials are used.
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18. glidants, improve flow by reducing inter- particulate friction (e. g
glidants, improve flow by reducing inter- particulate friction (e.g. Fumed Silicon Dioxide BP) and lubricants, which reduce powder to metal adhesion (e.g. magnesium stearate).
To achieve good drug release the contents should be readily wetted and dispersed by biological fluids.
The factors in the formulation which control drug release are the natures of the active ingredient and the adjutants.
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19. It has been demonstrated that the smaller particles of drug give higher blood levels than the same dose given as larger particles. This is because the surface area of the drug IS greater the smaller the particle size and this influence solution rate. This can not be utilized to improve availability in all cases (particle aggregatatin)
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20. The adjuvants are often described as the inert components
The adjuvants are often described as the inert components. In release terms (they can frequently play an active role. The major component of a mixture after the active drug is usually the diluent. Insol drugs are mixed with soluble diluents, in order to make the mixture more hydrophilic. Soluble drugs can be mixed with insoluble diluents e.g. starch, in order to avoid competition for solution.
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21. A formulation has to be designed for both good machine performance and good release properties. Some of the materials used to improve the filling performance, e.g. lubricants, magnesium stearate, are hydrophobic in nature, thus tending to slow down release. This effect can be minimized by using mathematical optimization techniques or by the inclusion of a wetting agent, e.g. sodium lauryl sulphate, into the mix.
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22. Formulation of non-powders for filling
Granules & pellets
particles should be as near spherical in shape as possible.
Granules are produced by granulation and tend to be more
irregular than pellets which are produced by a coating or
Micro-encapsulation technique. Both are often formulated to
produce modified release patterns. Uniform filling depends on the granules or
pellets being free flowing, regular in shape and size to give uniform packing
and non-friable to reduce dust.
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23. Tablets are filled into capsules either to
1-Produce special release forms, or
2- to separate incompatible ingredients.
For ease of filling the tablets need to be smooth preferably film coated which also reduce dust, and of a diameter and shape that will easely fit into a capsule body.
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24. Semisolids
Mixtures for filling need only be ‘liquid when filled and should be ‘solid’ when inside capsule. This is achieved by using mixtures which are either thermosoftening or thixotropic in nature .
They are liquefied for filling by either heat or shearing forces. The equipment is the same except that they have a heated hopper with a stirrer to hold the formulation which is dosed into the capsule through a volumetric pump.
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25. The semisolid filling is a means of safely handling toxic drugs as it reduces cross contamination associated with the filling of powders. For potent drugs in which uniformity of fill weight and content can be improved because of the use solutions and volumetric-dosing pumps.
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26. Labile materials can be incorporated into a matrix which reduces moisture and oxygen ingress. The release rate of drugs can simply be varied from rapid to prolonged by using excipients with different melting points and HLB vaIues.The more hydrophobic the base, the slower the rate of release. It provides a system for handling liquid mixes which every pharmaceutical manufacturer can perform in-house and not have to go out to a third party contractor.
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27. Formulation factors affecting release from hard gelatin capsules
Active ingredient
physicochemical properties such as solubility, melting point, crystalline form, (Most of properties of the active ingredient are beyond the control of the formulator) but one factor which can be modified is its particle size. The rate of absorption for several drugs is governed by their particle size. The blood levels obtained demonstrated that the smallest particle size gave the maximum blood level. (solution rate is directly proportional to the surface area of drug.
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28. Diluent described as an inert material added to a formulation to increase the volume of the mixture .diluents are not always inert as was demonstrated in the case of the reformulation of diphenyl hydantoin changing the diluent from calcium sulphate to lactose had a significant effect on the bioavailability.
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29. The diluent should be chosen with reference to the solubility and proportion of the active ingredient.
the soluble drug chloramphenicol, it has been shown that an increase in the quantity of lactose in the formulation decreased its dissolution rate (lactose is readily soluble it passes into, solution preferentially and thus the dissolution rate measured is that of chioramphenicol in saturated lactose solution.)
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30. Perhaps in the case of a readily soluble drug an insoluble diluent such as starch should be chosen. On disintegration of the capsules the starch grains would help the powder mass to break up without interfering with the solubility of the active ingredient.
Glidants and lubricants are added to improve the filling properties of the powder mixture( hydrophobic). A study on the dissolution rate of chlordiazepoxide formulations with three levels of magnesium stearate, 0, 1 and 5% (sec Fig. 19.4). They found that the dissolution was greatly reduced at the highest level of magnesium stearate.
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32. Wetting; effects of porosity and the addition of surfactants
the dissolution rate of the poorly soluble benzoic acid presented as a loose powder, and the same quantity of powder filled into a size 00. and a size 1capsule. The slowest dissolution rate was obtained with the size1capsule in which the powder is most tightly packed. They overcame this problem by adding 0.5% of polyol surfactant into the formulation. due to an increase in the deaggregation rate of the material.
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33. The type of filling machine used can affect drug release
If hydrophobic compounds have to be included they overcome its effect by the addition of wetting agents, surfactants at levels of 0.1—0.5%. Another solution by the use of soluble lubricants such as sodium stearyl fumarate which has been recently developed.
The type of filling machine used can affect drug release
A system, drug, lactose plus magnesium stearat 0% or 5%. This was filled into capsules at a ‘normal packing’ and a ‘dense packing’ and measured the dissolution rate. They showed that the denser packing reduced the dissolution rate and also added to the effect of the magnesium stearate (see Fig.
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35. II. Soft Gelatin Capsules
Abbreviated to soft gels.
Prepared from shells of gelatin to which glycerin
or a polyhydric alcohol as sorbitol is added to
render gelatin elastic or plastic-like.
N.B. The ratio of plasticizer to dry gelatin determines the “hardness” of the shell and can vary from 0.3 – 1 for a very hard shell to 1 – 1.8 for a very soft shell.
Shapes: oblong, elliptical or spherical in shape.
Contain liquids, suspensions,
pasty materials or dry powders.
Usually prepared, filled, and sealed in a continuous operation using specialized equipment.
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36. Examples of Soft Gelatin Capsules
Suppositories
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37. Advantages:
Useful when it is desirable to seal the medication within the capsule. The drug may hydrolyze or oxidize on long term storage.
drug poorly soluble in water or gastric juice and the bioavailability from some solid dosage forms might be poor.
can be protected from the environment by solution or dispersion in oil and encapsulation by gelatin. (resist gaseous diffusion and contain little labile water.)
The capsules are especially important to contain liquid drugs or drug solutions → rapid release of the contents with enhanced bioavailability.
Volatile drug substances or drug materials especially susceptible to deterioration in the presence of air may be better suited to a soft gelatin capsule.
Soft gelatin capsules are handsome and are easily swallowed by the patient.
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38. 1 -high dose of a poorly compressible drug may be difficult to form
During the development of a new medicinal product, many problems may be experienced by the pharmaceutical scientist. For example:
1 -high dose of a poorly compressible drug may be difficult to form
into tablets and there may be capping problems in production.
There may be powder flow or mixing problems and the dose of the drug in each dosage unit may not be uniform.
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39. Disadvantages:
Soft gelatin capsules are not easily prepared except on a large scale and with specialized equipment.
They are an expensive dosage form, when compared with direct compression tablets or hard shell capsules.
There is a more intimate contact between the shell and its liquid contents than exists with dry-filled hard gelatin capsules, which increases the possibility of interactions.
Not adaptable to incorporation of more than one kind of fill into the same capsule (compare with hard shell capsules).
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40. SOFTGELS CAN BE FORMULATED TO PRODUCE DIFFERENT DRUG DELIVERY SYSTEMS
Orally administered : containing solutions or suspensions that release their contents in the stomach in an easy way to swallow. (most common.)
2.Chewable : a highly flavoured shell is chewed to release the drug liquid fill matrix.
3.Suckable : consist of a gelatin shell containing the flavoured medicament to be sucked and a liquid matrix or just air inside the capsule.
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41. 4. Twist-off : designed with a tag to be twisted, thereby allowing
access to the fill material.
It can be very useful for unit
dosing of topical medication,
inhalations, or for oral dosing of a pediatric product.
5. Meltable : designed for use as 'patient-friendly' pessaries or suppositories
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42. PREPARATION OF SOFT GELATIN CAPSULES
Before the encapsulation process takes place, there
are two sub processes that are often carried out
simultaneously, yielding the two components of a
soft gel.
(a) The gel mass which will provide the soft gel shell,
(b) The fill matrix for the contents.
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43. Rotary Die Process 1. Gelatin ribbon 2. Rotary die 3. Filling Wedge
4. Filled capsule
5. Webbing
6. Pumping mechanism
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44. 11/17/2019

45. Formulation of the gelatin shell Gelatin
To produce shells with a greater flexibility than hard gelatin capsules it is necessary to control the viscosity and bloom strength of the gelatin used in production. If the viscosity of gelatin solution is too low, thin, low strength shell is produced with disadvantage of requiring prolonged drying. If the viscosity of the gelatin solution is too high a thick film is produced which may be too hard and brittle for this application.
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46. The mechanical properties of the gelatin shells are controlled by choice of gelatin grade and by adjusting the concentration of plasticizer in the shell.
Plasticizers
The main plasticizer used for soft gelatin capsules is glycerol. Sorbitol and propylene glycol have also been used but they are normally added in combination with glycerol. Plasticizers are added in relatively large concentrations compared with the amounts added to HGC& tablets. The greater the plasticizer content the greater the flexibility of the shell.
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47. Plasticizer concentrations can be expressed as parts of dry plasticizer to 1 part of dry gelatin. In practice these ratios vary widely between 0.3 and low ratios between 0.3 and 0.5 are used for oils’ liquid fills, between 0.4 and 0.6 for oily fills with added surfactant and between 0.6 and 1.0 for water-miscible fills and chewable capsules
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48. Water
The desirable water content of the gelatin solution used to produce a soft gelatin capsule shell depends on the viscosity of gelatin used and ranges between 0.7 and 1.3 parts of water to each part of dry gelatin, with a 1: 1 ratio being typical. Demineralized water is used.
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49. Preservatives
These have traditionally been added to prevent mould growth in the gelatin shell. Potassium sorbitate and methyl, ethyl and propyl hydroxybenzoate (methyl-, ethyl- and propylparaben) are common additives. Current research has shown that the free water content of normal capsule shells is too low to support the growth of micro-organisms and the use of these preservatives is unnecessary.
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50. Colours
A wide range of colours can be incorporated into soft gelatin shells water-soluble dyes (both synthetic and vegetable, insoluble inorganic and organic pigments and lakes.
Opacifiers
Titanium dioxide is the most common. It is added in concentrations of about O-O.5%.
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51. Enteric treatment
Enteric properties can be imparted to soft gelatin shells by coating with 4% cellulose acetate phthalate.
Formulation of the capsule contents
. These range through suspensions and pastes to drugs in solution in oils, self-emulsifying oils and water-miscible liquids. By far the most common situation is to fill them with liquid. Almost an’ non-aqueous liquid drug or powdered solid made into a suspension can be filled into soft gelatin capsules.
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52. Limitations for fill materials
Drugs or excipients containing high concentrations of water or other gelatin solvents cannot be incorporated. It is not recommended to fill emulsions (whether they be o/w or w/o) since they are unstable and will crack as the water is lost from the shell in the manufacturing -process.
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53. 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 have a tanning effect on the gelatin, affecting the subsequent solubility of the shell. Aldehydes must also be avoided since these have a tanning action on the proteins of the gelatin shell.
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54. Bioavailability aspects of soft gelatin capsules
Acid-soluble drugs, dissolved or dispersed in water-miscible vehicles, are distributed quickly throughout the stomach. Suspended particle dissolve quickly and the bioavailability is good .
Soft gelatin capsules have yielded similar blood level curves to those produced by liquids.
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55. Mean serum theophylline concentrations in 14 subjects after a crossover study comparing soft gelatin capsules (polyol base) with an oral aqueous non-alcoholic solution
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56. Acid-insoluble compounds administered as a solution in a soft gelatin capsule precipitate as a fine suspension in the stomach. The surface area is high and the precipitate quickly redissolves to give a solution with optimum bioavailability
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57. Figure shows the mean serum temazepam levels in five subjects receiving 20 mg of temazepam in a cross-over study using tablets (Wyeth) and SEG capsules (polyol fill). The improved bioavailability, of temazepam changed the therapeutic effect of a tranquillizer to a hypnotic.
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58. Plasma concentration vs. time O: SGC ●:Tablet
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59. EVALUATION OF COMMERCIAL CAPSULES:
1. UNIFORMITY OF WEIGHT AND CONTENT OF ACTIVE INGREDIENT:
To control the uniformity of actual drug content in relatively little diluent or excipient present, it may be enough to control the uniformity of weight.
In the case of more potent, low-dose drugs, less than 2mg or less than 2% by weight of the total weight of the capsule fill, the control of uniformity of weight does not offer sufficient assurance of the uniformity of drug content, since adequate blending may not have been achieved. In this case a content uniformity test should be performed.
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60. (2) DISSOLUTION:
Disintegration of a tablet or dissolution of a capsule shell does not imply complete dissolution of the active ingredient.
Since the dissolution of a drug is considered to be an essential step in the absorption process, the availability of a drug for absorption from a dosage form largely depends on the drugs dissolving in GIT fluids.
Often dissolution is the rate-limiting step (i.e., the slowest step) in the over-all absorption process.
Various factors, including the physicochemical properties of the drug, how it is formulated, and how it is processed can significantly affect drug availability.
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61. In general, the capsule is placed in a basket formed from a screen.
The dissolution test is carried out using the dissolution apparatus official in both the U.S.P. and N.F.
In general, the capsule is placed in a basket formed from a screen.
A stirrer shaft is attached to the basket, and the basket is immersed in the dissolution medium and caused to rotate at a specified speed.
The dissolution medium (900 ml, unless otherwise specified in the individual monograph) is held in a covered 1000 ml vessel made of glass or other transparent material.
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62. The lid has four holes: two to accommodate the stirrer shaft and a thermometer, two for sampling and fluids exchange.
The dissolution medium is maintained at 37° ± 0.5 by means of a suitable constant-temperature water bath.
The stirrer speed and type of dissolution medium are specified in the individual monograph.
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