CAPSULES

1
CAPSULES
2
Raw Materials For Gelatin Capsules

• Gelatin
• 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.

3

• 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.

4

• 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
5

• 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 (150-200bloom).
• Gelatin Viscosity control the thickness of film
  or sheet.

6

• 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.

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.

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.

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.

10
(No Transcript)
11
Manufacture

• 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.

12
Preparation of the capsule shell for hard
gelatin capsules
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.

14
Capsule filling machine
15

• 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.

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.

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.

18

• 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.

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)

20

• 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.

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.

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.

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.

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.

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.
  

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.

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.

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.

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.)

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.

31
(No Transcript)
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.

33

• If hydrophobic compounds have to be included they
  overcome its effect by the addition of wetting
  agents, surfactants at levels of 0.10.5.
  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.

34
(No Transcript)
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.

36

Examples of Soft Gelatin Capsules
Suppositories
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.

38

• 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.

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).

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.

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
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.

43
Rotary Die Process
1. Gelatin ribbon 2. Rotary die 3. Filling
Wedge 4. Filled capsule 5. Webbing 6. Pumping
mechanism
44

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.

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.

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 1.0 . 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

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.

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.

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.

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.

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.

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.

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.

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

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

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.

58

• Plasma concentration vs. time
• O SGC ?Tablet

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.

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.

61

• 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.

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.