Hard gelatin
`capsules today –
`and tomorrow
`
`Sven Stegemann, Capsugel Bornem
`
`2nd edition 2002
`
`(cid:38)(cid:68)(cid:83)(cid:86)(cid:88)(cid:74)(cid:72)(cid:79)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:20)(cid:19)(cid:22)(cid:22)
`
`

`

`Hard gelatin capsules today –
`and tomorrow
`
`Dr. Sven Stegemann, Capsugel, Bornem
`
`The capsule is one of the oldest dosage forms in
`pharmaceutical history, known to the ancient Egyptians.
`[1] The earliest European reference is contained in a
`travel account of 1730 which mentions the pharma-
`cist de Pauli from Vienna, who produced oval-shaped
`capsules in the hope of covering up the unpleasant taste
`of the pure turpentine he prescribed for people suffering
`from gout. [2]
`
`A further 100 years were to pass before the first gelatin
`capsule appeared. The first patent for such a product
`was granted in 1834 to the pharmacist Joseph Gérard
`Auguste Dublanc and the pharmacy student François
`Achille Barnabé Mothès. [3] Mothès, who ended his
`collaboration with Dublanc in 1837 [4], continued to
`work on improving the gelatin capsule and to take out
`patents for the manufacture and use of capsules.
`
`Mothès' invention was so successful that, by the
`following year, capsules were being produced in many
`different parts of the world. [5] Eventually, this result-
`ed in several more patents for gelatin capsules being
`taken out by others, not least to circumvent those held
`by Mothès.
`
`The Frenchman Jules César Lehuby was suc-
`cessful in this strategy and, in 1846, was granted a patent
`for his 'medicine coverings', which formed the basis
`of his future inventions.[6] He was also the first to
`suggest two-piece capsules, which he produced by
`dipping silver-coated metal pins into a gelatin solution
`and then drying them.
`
`Despite the great interest in Lehuby's patent, which
`describes the principle of hard-gelatin capsule man-
`ufacturing that is still used today, technical difficulties
`in manufacturing the separate fitted sections – the body
`and the cap – stopped further development of this
`dosage form for another century.
`
`It was in 1931 that Arthur Colton, on behalf of
`Parke, Davis & Co., succeeded in designing a machine
`
`which simultaneously manufactured both bodies and
`caps and fitted them together to form a hard gelatin
`capsule. [7] It is amazing to realise that a machine orig-
`inally built in 1931 still represents the basic design of
`today's machinery. Only minor modifications have
`been made to it since that time, in the interests of
`improved product quality and greater technical efficiency.
`
`Hard gelatin capsules –
`a growing market
`
`Hard gelatin capsules are a modern dosage form
`for medicinal use, stemming from the increased empha-
`sis on pharmacokinetics found in drug development
`today. This has considerably expanded the range of
`possible formulations utilising hard gelatin capsules as
`a simple dosage form for oral drug delivery. Nowadays,
`modern capsule-filling machines can produce up to
`
`Figure 1: Comparison of new chemical entities formulated
`as hard gelatin capsules and tablets since 1982.
`
`3
`
`

`

`200,000 capsules an hour and are also capable of fill-
`ing a number of different substances in a single pro-
`cess run.
`
`These developments probably account for the fact
`that use of the hard gelatin capsule has grown steadi-
`ly over the years. Between 1970 and 1975, capsules
`showed sales growth rates ranging from 8% to 21%
`in the four largest European markets. [8]
`
`And it is a continuing trend. The hard gelatin cap-
`sule is increasingly being chosen for new medicines
`in solid oral dosage form. In 1982, only 17.5% of
`newly-licensed products were presented as hard
`gelatin capsules. By 1996 the figure had already
`reached 34% (Figure 1).
`
`Hard gelatin capsules
`as a dosage form
`
`In the development of new medicines, there are sev-
`eral problems to be solved. As well as the formulation,
`and its important stability and release-characteris-
`tics,control and reproducibility of the production pro-
`cess are other factors to be taken into account and,
`increasingly, research costs and development time-
`frames have also to be considered.
`
`When it comes to a decision at the end of phase
`II, which dosage form will be developed for the mar-
`ket, high production costs of hard gelatin capsule
`products are generally assumed. This assumption is
`valid if the production costs are limited to the comparison
`of the excipient costs only. When taking into account
`the total manufacturing costs, which include the hid-
`den costs coming from process equipment, GMP
`space required, total production time, in-process-
`controls, analytical, cleaning and validation work the
`comparison easily turns out in favor of the capsule for-
`mulation [9].
`
`More. As the development costs for new medicines
`continue to rise, it is becoming imperative to obtain inter-
`national registration for the formulation. Ensuring that
`all new entities conform to the various pharmacopoeias
`and regulatory requirements is yet another task for the
`formulation scientist. Companies are aiming at achiev-
`ing – reproducibly – a consistency of product quality
`acceptable on a worldwide scale.
`
`Pharmacopoeial monographs
`
`When talking about hard gelatin capsules, powder
`and granular fillings are what spring to mind. These prod-
`ucts still account for most hard gelatin capsules on the
`market, which is why the monograph on capsules in
`the German Pharmacopoeia DAB 10 (1996) describes
`the fillings for hard gelatin capsules as 'normally in solid
`form (powder or granules)'.
`
`In fact, historically, the first hard gelatin capsules were
`actually developed for liquid medicines. Thanks to the
`gelatin capsule, it was possible to formulate a new
`dosage form for liquid balsam copaivae, which had been
`used during the Napoleonic wars as a cure for vas-
`cular diseases. This was of great importance, as the
`substance causes severe nausea if taken as an oral
`solution. [10]
`
`Now, the German monograph on capsules urgent-
`ly needs revision in the light of the increasing number
`of new-wave hard gelatin products coming onto the
`market which include fillings in sustained release pel-
`lets and – as per the tradition – in liquid and semi-solid
`form.
`
`The European Pharmacopoeia (Eur. Ph.) describes
`capsules as follows: 'Capsules are solid preparations
`with hard or soft shells of various shapes and capac-
`ities, usually containing a single dose of active ingre-
`dient. They are intended for oral administration.'
`
`Also included in its monograph is a description of
`hard capsules: 'Hard capsules have shells consisting
`of two cylindrical sections, one end of which is round-
`ed and closed, the other open. The active ingredient
`or ingredients, usually in solid form (powder or gran-
`ules) are filled into one of the sections which is then
`closed by slipping the other section over it. The secu-
`rity of the closure may be strengthened by suitable
`means.'
`
`A similar general description of the capsule can also
`be found in the US Pharmacopeia (USP 24). It defines
`capsules as solid dosage forms in which the active ingre-
`dients are sealed in a hard or soft container or shell.
`In contrast to the European monograph, the USP also
`mentions starch and other substances used in the pro-
`duction of the shell.
`
`Shapes of hard gelatin capsules
`
`As will be pointed out in the following chapters, the
`simplicity of hard gelatin capsule formulation and
`manufacturing as well as the versatility of this dosage
`form substantially supports these requirements.
`
`The general descriptions given in pharmacopoeias
`hardly do justice to the variety of shapes on offer
`today. These have been developed over the last few
`years as a result of increased demand and requirements,
`
`4
`
`

`

`Body and cap are designed to fit only if the two parts
`are precisely in line; the slightest sideways movement
`of the capsule halves during the closing process results
`in splitting or denting. This problem was solved with
`the invention of a tapered rim on the body section of
`the capsule (Figure 4).
`
`2 1
`
`3
`
`closed
`
`temporarily
`closed
`
`open
`
`1. The tapered rim prevents splitting and denting
`of the capsule
`2. The notches prevent premature opening
`of the capsule
`3. The rim closes the filled capsule safely
`(SNAP-FIT™ principle)
`
`Figure 3: Recent hard gelatin capsule with features
`(notches or dimples) for pre-closing; closing features
`(e.g. SNAP-FIT™ ) and tapered rim (e.g. CONI-SNAP™).
`
`During the closing process, the cap's position can
`be adjusted to a certain extent by means of the tapered
`rim, so enabling the capsule halves to fit properly. The
`approach reduces the number of defects due to split-
`ting or denting by an average of 88%. [11]
`
`To prevent pressure build-up in the capsule owing
`to the speed of the closing process, the airvent clo-
`sure has come onto the scene. This allows for the escape
`of air between body and cap. The principle of all air-
`vent closures on the market is to reduce the air space
`left between body and cap after filling. Examples such
`as SNAP-FIT™ work by flattening the body rim.
`
`Another recent demand has been for capsules that
`can hold liquid or semi-solid substances (LICAPS™).
`LICAPS™ is a gelatin capsule exclusively designed to
`optimize liquid filling by a special body design and the
`missing air-vent to prevent leakage before sealing
`
`5
`
`Capsule shoulder
`
`Capsule cap
`
`Capsule body
`
`open
`
`closed
`
`Figure 2: Standard hard gelatin capsule.
`
`aided by the introduction of fully-automatic filling
`machines. In a single operation, automatic capsule-
`filling machines line up and rectify the hard gelatin
`capsules, separate body and cap, fill the body, join cap
`and body together (for closing), and eject the filled cap-
`sule.
`
`Where capsule design is concerned, its main fea-
`tures are its two fitted sections, body and cap. In the
`beginning capsules had smooth edges (Figure 2),
`which could slide freely against each other.
`
`During manufacture, pressure frequently builds up
`within the capsules as a result of the speed of the clos-
`ing process and of mechanical strain during produc-
`tion and packaging, and this often results in capsules
`of varying length, and a risk of the capsules bursting
`after filling. Two encircling grooves were introduced,
`one placed around the body just below the rim, the
`other around the cap just under the top to interlock
`when body and cap are pressed together (Figure 3),
`ensuring firm closure and equal lengths.
`
`However, this does not in itself resolve the problem
`with the only lightly fitted together cap and body that
`tend to fall apart during transport or in the filling
`machines. This problem needed the invention of notch-
`es on the cap just below the rim, which allow tempo-
`rary closure of the sections. The capsule is held secure-
`ly closed during transportation but can easily be
`opened by the filling machine (Figure 3).
`
`As the capacity of filling machines increased, pri-
`ority turned to improving hard gelatin capsules in
`terms of their safe and speedy closure following filling.
`
`

`

`1
`
`1
`
`Figure 4: Design of the tapered rim ➀ of the capsule body
`(e.g. CONI-SNAP™).
`
`(Figure 5). Moreover, the six dimples maximize the
`area for sealing of the two-piece hard gelatin capsule
`by a hydroalcoholic fusion process described later in
`this article (see LEMS™).
`
`Primary
`barrier
`
`Sealing
`zone
`
`No air vent
`
`Dimples
`
`Figure 5: Features of the LICAPS™.
`
`Especially for blinding purposes of clinical trials,
`hard gelatin capsules that are virtually impossible to
`re-open after filling are required. There is available the
`DBcaps™ capsule with a cap covering most of the body
`so that only the rounded end of the body is visible, which
`impedes opening (Figure 6).
`
`DB caps™ are hard gelatin capsules whose size,
`colour and shape meet the worldwide requirements
`
`6
`
`Figure 6: Hard gelatin capsule with the cap that covers
`most of the body (e.g. DB caps™ ).
`
`of double-blind clinical trials. They are available in
`three different sizes and cater for single doses or for-
`mulations up to a diameter of 9 mm. Different neutral
`colours recognized for blinding are available, which are
`internationally accepted for medicinal use.
`
`The capsules cannot be reopened once they have
`been closed. This ensures that the administration of
`placebo, test drug and reference preparations, or of
`sustained-release doses is consistently accurate and
`can not be identified by the doctor or patient. Capsules
`for double-blind trials are also available in small quan-
`tities and hospital pharmacists are therefore in the
`position to provide individual test medications.
`
`Table 1 lists the capsule sizes on the market and
`their respective filling capacities.
`
`Capsule Capsule Capacity in mg
`size
`volume
`powder density
`in ml
`0.6
`0.8
`1.37
`822
`1096
`1.02
`612
`816
`0.91
`546
`728
`078
`468
`624
`0.68
`408
`544
`0.50
`300
`400
`0.37
`222
`296
`0.30
`180
`240
`0.21
`126
`168
`0.10
`78
`104
`
`000
`00el
`00
`0el
`0
`1
`2
`3
`4
`5
`
`1.0 1.2 g/ml
`1370
`1644
`1020
`1224
`910
`1092
`780
`936
`680
`816
`500
`600
`370
`444
`300
`360
`210
`252
`130
`156
`
`Table 1: Examples for hard gelatin capsule dimensions
`and filling capacities.
`
`

`

`Even more recent developments are capsules
`specifically designed for preclinical research (PC caps™).
`
`PC caps™ are capsules for preclinical and animal
`trials. They could be described as size 9 capsules. The
`dimensions of the closed capsule are 7.18 mm in
`length and 2.06 mm in diameter, with a volume of 0.2
`ml. They are especially suitable for administering an exact
`quantity of substances to rodents. They help to avoid
`a number of stress factors such as unpleasant taste,
`irritation of the mucous membranes and regurgitation,
`so reducing the overall strain on the animal during the
`experiment.
`
`Hard gelatin capsules
`with powder filling
`
`The production process
`Immediate-release capsules with a simple powder
`filling are the best-known type of hard gelatin capsules.
`They require only a few manufacturing process steps.
`Usually, it is easy to mix the active substance with excip-
`ients and to fill the mix into the capsules.
`
`Depending on the process a light pre-compression,
`to form a so-called 'plug', might also be necessary. The
`force used for pre-compression is normally between
`20N and 30N, far below the usual pressure for tablets
`of 3 x 104N [12]. In comparison with conventional
`tablet production, capsule production does not require
`expensive and time-consuming operations like repeat-
`ed mixing and sieving, or granulation and compres-
`sion (Table 2).
`
`In contrast, other types of oral dosage forms might
`also require a considerable number of excipients as
`
`Capsules
`1. Weighing
`2. Preparing ingredients
`3. Mixing
`4. Filling into capsules
`5. Packing
`
`Tablets
`1. Weighing
`2. Preparing ingredients
`3. Mixing
`4. Granulating
`5. Drying
`6. Sieving
`7. Addition of lubricants/
`mixing/sieving, as necessary
`8. Compression
`9. Packing
`
`Table 2: Production process operations in the manufacture
`of tablets and capsules.
`
`well as additional processing steps. This results in
`higher costs, partly due to the cost of excipients, but
`also to increased analysis and validation costs, which
`can add as much as 15% to the overall cost of pro-
`duction. [13]
`
`Use of excipients
`One of the major initiatives of the pharmaceutical
`industry to reduce production costs in the past decade
`was dedicated to the reduction of the raw materials
`and its stocks. The average number of excipients in
`tablet, sugar coated tablet and hard gelatin capsule
`formulations are shown in Table 3. Hard gelatin cap-
`sules usually require between one and four excipi-
`ents, while some five to eight are needed in tablet for-
`mulation. Sugar coated tablets require at least nine excip-
`ients, since a special formulation is used for the coat-
`ing [14]. Moreover, the addition of any excipient car-
`ries the potential risk for promoting degradation of the
`drug molecule by an interaction with its functional
`groups or residues [15].
`
`Number
`of excipients
`1-4
`5-8
`9 or more
`
`Capsules
`
`Tablets
`
`18
`5
`-
`
`3
`15
`5
`
`Sugar coated
`tablets
`-
`-
`6
`
`Table 3: Number of excipients needed for the manufacture
`of capsule, tablet and sugar coated tablet products.
`
`Considering that more and more tablets are simi-
`larly undergoing a costly coating process, the number
`of excipients and operations involved in their produc-
`tion may actually be greater. It can therefore be
`assumed that, in a large number of cases, production
`costs for hard gelatin capsules are the same as – or
`even less than – those for tabletting. Yet the miscon-
`ception remains that hard gelatin capsules are an
`expensive form of medication.
`
`As well as diluents and lubricants, other excipients
`used in the manufacture of hard gelatin capsules
`include colloidal silicon dioxide for improved flow char-
`acteristics and reduced adhesion of the substance to
`metal parts in the filling machine, and disintegrants and
`wetting agents to facilitate release.
`
`Some excipients might have several functions.
`Talcum, for instance, serves as a lubricant in con-
`centrations below 5%. At higher concentrations, it is
`mainly considered a filler. [16] And besides being an
`
`7
`
`

`

`excellent filler, microcrystalline cellulose also serves as
`a disintegrant. [17]
`
`In addition, the functions of excipients in hard
`gelatin capsules can be different from their functions
`in tablets. Starch, which is commonly added to tablets
`as a disintegrant owing to its macerating properties of
`5% to 10%, might be used as a filler in hard gelatin
`capsules because the macerating properties are not
`strong enough to really disintegrate the lightly com-
`pressed substances in hard gelatin capsules. [16]
`
`Diluents
`➔ Improved plug formation and compression
`• Mannitol
`• Microcrystalline cellulose
`• Lactose
`• Starch 1500
`• Corn starch
`
`Lubricants
`➔ Improved flow properties and reduced powder adhesion
`to metal parts
`• Magnesium stearate
`• Stearic acid
`
`• Glyceryl monostearate
`
`Glidants
`➔ Improved powder flow properties
`• Aerosil
`• Talcum
`
`Disintegrants
`➔ To ensure disintegration of powder mixture
`• Croscaramellose
`• Corn starch
`• Crospovidone
`• Starch 1500
`• Sodium glycyl starch
`• Alginic acid
`
`Wetting agents
`➔ Improved water penetration into powder mixture
`• Sodium lauryl sulphate
`• Tween 80
`
`Table 4: Excipients used in formulations of immediate-
`release hard gelatin capsules.
`
`The characteristics of many excipients depend on
`storage conditions (temperature or humidity, for
`instance). Excipients that show hysteresis in their
`sorption-isotherms – as, for example, gelatin, starch
`or microcrystalline cellulose – might show different
`levels of absorbed water on their surfaces even when
`subject to the same humidity in the controlled condi-
`tions of the production room, due to individual stor-
`age conditions. It is therefore advisable to dry these
`excipients before use. [17]
`
`The stability of many compounds is pH depen-
`dent. Acetylsalicylic acid for example is a compound
`that is most stable at a pH 2.4. In a dry formulation
`acetylsalicylic acid is in contact with the surface of the
`particles of all the other excipients. As the humidity in
`the environment will always lead to absorption of
`moisture on the surface, the particles will be sur-
`rounded by a mono-layer of a saturated solution. To
`optimize product stability, the excipients need to be
`selected according to their surface acidity in the dry
`state (pH eq) rather than to add buffer agents [18-21].
`
`The most common excipients used for the formu-
`lation of drugs in hard gelatin capsules, along with their
`functions, are listed in Table 4.
`
`When formulating hard gelatin capsules for imme-
`diate- release, attention should be paid to establish-
`ing a reproducible product dissolution profile. In the fluid
`environment of the stomach, the shell of the capsule
`starts to soften and dissolve within one or two min-
`utes, and comes apart at its weakest point, the cap-
`sule shoulder (see Figure 2).
`
`Consequently, the uncompressed or only slightly com-
`pacted content comes into contact with water. If the
`capsule formulation is sufficiently hydrophilic or con-
`tains disintegrant or a wetting agent, water can pen-
`etrate the powder. The capsule disintegrates and its
`contents are released. Hard gelatin capsules are fully
`disintegrated within about 10 minutes. [22, 23]
`
`To sum up, we would like to stress again that hard
`gelatin capsules are simple in their formulation and pro-
`duction and that their disintegration is both known and
`controllable. Hard gelatin capsules are actually easi-
`er and quicker to formulate and produce, whatever the
`batch size, compared with other solid oral dosage forms.
`Indeed, by using hard gelatin capsules it is possible
`to produce small or very small batch sizes on manu-
`al or semi-automatic filling machines.
`
`This is of major advantage to the pharmaceutical
`industry when there is only a very limited quantity of
`active substance available for formulation and initial clin-
`ical testing. Dispensing pharmacies and clinics also gain
`by using hard gelatin capsules when they have to
`produce small quantities or when they have to prepare
`a single prescription as a solid oral dosage form.
`
`Hard gelatin capsules are a means of providing
`patients with optimum therapy. They can be produced
`as individual medication for a single patient, to provide
`specific doses and combinations of substances, or to
`improve the patient's compliance. It is also possible
`to produce even complicated medications for clinical
`trial purposes.
`
`8
`
`

`

`Product requirements
`One of the key advantages in formulating as imme-
`diate- release hard gelatin capsules is that it is a way
`of ensuring that each capsule contains the exact dose
`(Ph. Eur 2.9.6. Uniformity of content of single-dose prepa-
`rations, and Ph. Eur 2.9.5. Uniformity of mass of sin-
`gle-dose preparations), and that this dose is released
`as quickly as possible to ensure bioavailability (Ph. Eur
`2.9.1. Disintegration of tablets and capsules).
`
`For optimum machine-filling performance, the pow-
`der must be of the right flow and density; the densi-
`ties of the excipients and the drug should therefore be
`similar [24]. The flow is of special importance as prob-
`lems can arise not only from poor flow properties but
`also from flow properties that are too efficient; for
`example, when a dosator, type of filling machine is used
`and the height of the powder bed varies. [25] In addi-
`
`tion, the powder should show only minimal adhesive
`characteristics. [24]
`
`High speed filling machines today mainly use two
`filling principles referred to as “dosator type” or “dos-
`ing disk or tamping type”. The dosator principle uses
`a dosing tube that dip in a powder bed that is normally
`two times higher than the final plug length. During the
`dipping and by the dosator piston movement, the
`powder is densified to form a cohesive plug. The dos-
`ing tube transfers the plug to the capsule body for ejec-
`tion. The dosing disk principle is based on filling cham-
`bers that are bored into the dosing disk. Powder flows
`into the filling chambers followed by a slight com-
`pression by a tamping punch, which is repeated five
`times before the plug is ejected into the capsule body
`through the hole of the tamping disk.
`
`To address the need of each company and their spe-
`cific products, the capsule filling machine manufacturer
`
`Output caps / h
`
`24.000
`42.000
`150.000
`
`3.000
`
`25.000
`
`6.000 – 40.000
`8.000 – 85.000
`
`Dosing principle
`Machine
`Bosch Further information : www.bosch.de
`GKF 400
`Dosing disk
`GKF 700
`Dosing disk
`GKF 2000
`Dosing disk
`Dott. Bonapace Further information : www.dottbonapace.com
`IN-CAP
`Auger
`Harro Höfliger Further information : www.hoefliger.de
`KFM III-C
`Dosator or dosing disk
`IMA Further information : www.ima.it
`ZANASI 6 / 12 : 25 / 40 Dosator
`ZANASI Plus 8 / 16 /
`Dosator
`32 / 48 / 70 / 85
`Dosator
`MATIC 60
`Dosator
`MATIC 90
`Dosator
`MATIC 120
`Dosator
`IMATIC 100
`Dosator
`IMATIC 150
`Dosator
`IMATIC 200
`Dosing disk
`IMPRESSA 130
`MG2 Further information : www.mg2.it
`SUPREMA
`Dosator
`MG COMPACT
`Dosator
`MG FUTURA
`Dosator
`PLANETA 100
`Dosator
`G 37/N
`Dosator
`G 70
`Dosator
`G 100
`Dosator
`G 140
`Dosator
`G 250
`Dosator
`Romaco-Macofar Further information : www.romaco.com
`CD 5 and 20
`Dosator
`6.000 – 20.000
`CD 40
`Dosator
`40.000
`CD 60
`Dosator
`66.000
`
`60.000
`90.000
`120.000
`100.000
`150.000
`200.000
`130.000
`
`48000
`6.000 – 96.000
`6.000 – 96.000
`100.000
`100.000
`70.000
`100.000
`140.000
`200.000
`
`Table 5: Capsule filling machines on the market and it major features.
`
`Products to be filled
`
`Powder, pellets
`Powder, pellets, tablets, liquids
`Powder, pellets, microtablets, tablets
`
`Powder, pellets, tablets
`
`Powders, pellets, tablets, liquids
`
`Powder, pellets, tablets, liquids
`Powder, pellets, tablets, liquids
`
`Powder, pellets
`Powder, pellets
`Powder, pellets
`Powder; pellets
`Powder, pellets
`Powder, pellets
`Powder
`
`Powder, pellets
`Powder, pellets, tablets, capsules, liquids
`Powder, pellets, tablets, capsules, liquids
`Powder, pellets, tablets, liquids
`Powder, pellets, tablets
`Powder, pellets, tablets
`Powder, pellets, tablets
`Powder, pellets, tablets
`Powder, pellets, tablets
`
`Powder, pellets, tablets
`Powder, pellets, tablets
`Powder, pellets, tablets
`
`9
`
`

`

`offer a wide range of full automatic capsule filling
`machines that range from 6.000 – 200.000 capsules
`an hour. Several of this machines are highly flexible and
`can fill different products in one cycle, which is espe-
`cially interesting for drug delivery systems with differ-
`ent release profiles or drug products. The most com-
`mon used capsule filling machines are listed in table 5.
`
`To predict the required capsule size as well as to
`estimate and adjust powder flow and compressibility
`if requested, the Carr’s Index is used [26].
`
`Tapped density - bulk density
`Carr's Index = ____________________________ x 100
`Bulk density
`
`A Carr’s index of < 15 % is referred to as a very good
`flow, while 16-26 % are good, 27 – 35 are fairly good
`and > 35 % the flow properties are considered as poor.
`
`Research by Heda demonstrated that there is no
`significant difference in the formulation requirements
`for a dosator or a dosing disk filling principle. However,
`the optimum Carr’s index for a dosator type was cal-
`culated with 25 – 35 %, while the optimum Carr’s
`index of a dosing disk type is between 18 – 30 %. [27].
`
`Decisions on the type and quantity of excipients such
`as diluents, disintegrants, lubricants and wetting agents
`are therefore of major importance in the formulation pro-
`cess. But, above all, the formulation depends on the
`required quantity of an active and its physico-chemi-
`cal properties.
`
`Now, to aid in this process, Capsugel has devel-
`oped a computer-based Expert System for the for-
`mulation of immediate-release hard gelatin capsules.
`This work has been carried out in conjunction with more
`than 30 pharmaceutical companies, as well as the
`Universities of London (Europe), Kyoto (Japan), and
`Maryland (USA) and some 50 other experts.
`
`At the heart of the system lie three databases. The
`first comprises data on products that are available on
`the market. The second contains data from publica-
`tions and from the experience of the experts involved,
`while the third is based around the results of experi-
`ments and mathematical and statistical calculations on
`the effect of single excipients on formulations, carried
`out by the participating university of London. [28]
`
`There now follows a briefing on the most important
`parameters and their effects on formulations of hard
`gelatin capsules.
`
`Important parameters for
`the formulation of hard gelatin
`capsules with powder formulation
`
`Compatibility with gelatin
`When starting to formulate a medicine in hard
`gelatin capsule form, the first thing to study is its com-
`patibility with the gelatin shell. Incompatibilities are
`known to occur; for instance, with certain substances
`that contain reactive aldehydes. The aldehydes can react
`with the gelatin by forming crosslinks.
`
`A recent review has shown that cross-linking is
`not inevitable, but depends on several mechanisms.
`[29] The main contributory factors are storage stress
`(high temperatures, high humidity, excessive light
`exposure) and the presence of aldehydes (for exam-
`ple, formaldehyde).
`
`In the case of reactivity of the gelatin, which con-
`sists of a mixture of water-soluble proteins, lysine
`residues are mainly responsible for cross-linking, either
`within a gelatin strand (intra-strand cross-linking) or
`between separate strands (interstrand cross-linking).
`
`It is sometimes possible to reverse the type of
`chemical reaction involved, but this will depend on the
`pH level or the presence of enzymes. It has been
`shown, for example, that reducing the release rate in
`in vitro dissolution tests bears no relationship to the
`in vivo dissolution rate and the consequent bioavail-
`ability of substances. [30, 31] However, adding the
`enzymes pepsin and pancreatin to the dissolution
`medium prevents the inhibitory factors from taking
`effect. [32] This result has led to the assumption that
`inhibited dissolution is due to the test conditions.
`
`The USP 24 propose therefore that pepsin (for acid
`media) and pancreatin (for alkaline media) can be
`added in dissolution tests aimed at establishing the like-
`ly in vivo dissolution properties (Two Tier Dissolution
`Test). Only in cases where the enzymes have been added
`and the test still shows poor dissolution should a neg-
`ative effect due to cross-linking be assumed.
`
`A further incompatibility can be caused by the
`water content of the gelatin shell. If a substance is high-
`ly hygroscopic, it might absorb water from the cap-
`sule shell. This process can lead to brittleness of the
`shell, which might break under mechanical strain. If the
`drug substance in the capsule is sensitive to humidi-
`ty the water content of the shell, which is normally
`between 13% and 16%, can lead to the degradation
`of the drug substances.
`
`10
`
`

`

`Doses
`
`The dose of the drug active that is to be formulat-
`ed is the main parameter for a suitable formulation. For
`low doses in the milligramme range, homogeneity of
`the substance within the powder has to be main-
`tained. For doses in excess of 100 mg or in the small-
`est suitable capsule size, the properties of the active
`are of key importance, as the quantities of excipients
`are minimal.
`
`High concentrations of drug active usually lead to
`difficulties during the filling process, proportional to the
`concentration of the active in the formulation. Problems
`at this stage can be prevented by a properly thought-
`through choice of diluents and adequate quantities of
`lubricants. [33]
`
`Doses over 600 mg in powder form are virtually
`impossible to put into capsules of acceptable size. It
`has, though, been possible to produce such doses in
`hard gelatin capsule form by increasing the density of
`the formulation; for instance, by granulation. Granulation
`usually leads to an improvement of parameters such
`as product flow. It is also possible to improve the dis-
`solution rate of substances by granulation, due to
`increased dispersion of the drug active in the granules.
`
`Shape of particles
`
`To achieve the specification for content uniformity
`on filling machines, it is vital to have an adequate
`powder flow. Poor powder flow is characterised by the
`formation of a central cavity ('rat-holing') when flow-
`ing out of a cylinder, while the powder at the edge remains
`static. [34]
`
`Product flow is mainly defined by the shape of the
`particles as well as by inter-particulate cohesion and
`surface films (sorption water). The fluidity of anisometric
`particles such as needle-shaped, plateshaped or pris-
`matic particles is peculiar, insofar as it not only follows
`the primary direction but also a secondary direction
`according to the orientation of the particles. [35] This
`is the reason why anisometric particles result in sig-
`nificant differences in the bulk and tap density. The
`mechanical vibration is strong enough to allow the par-
`ticles to gain a higher grade of order.
`
`Isometric – for example, round – particles are
`already in highly compact order, forming the most
`dense shape. [36] So, for hard gelatin capsules the drug
`substances and excipients should preferably be of
`isometric shapes. In the case of anisometric parti-
`cles, grinding or granulation should be considered.
`
`Solubility
`Solubility of the drug active and the excipients is the
`major contributory factor in disintegration and disso-
`lution. The more water-soluble the formulation, the
`quicker it disintegrates and releases the substance. In
`the case of substances which are poorly soluble in water,
`disintegration and release depend heavily on disinte-
`grants and diluents. [33]
`
`Particle size
`The particle size of the drug active is critically impor-
`tant to the homogeneity and fluidity of the powder. By
`decreasing the particle size the electrostatic charge
`increases. While leaving the filling funnel, this may
`lead to the formation