International Journal of Pharmacy and Pharmaceutical Sciences
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`ISSN- 0975-1491
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` Vol 9, Issue 10, 2017
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`Review Article
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`HPMC AS CAPSULE SHELL MATERIAL: PHYSICOCHEMICAL, PHARMACEUTICAL AND
`BIOPHARMACEUTICAL PROPERTIES
`
`SUTAPA BISWAS MAJEE*, DHRUTI AVLANI, GOPA ROY BISWAS
`
`
`
`Division of Pharmaceutics, NSHM Knowledge Campus, Kolkata-Group of Institutions 124 B L Saha Road, Kolkata 700053 West Bengal, India
`Email: sutapabiswas2001@yahoo.co.in
`
`Received: 14 Jun 2017 Revised and Accepted: 31 Aug 2017
`
`ABSTRACT
`
`The most common instability problem of gelatin capsules arises from negative impact of extremes of temperature and especially atmospheric
`relative humidity on the mechanical integrity of the capsule shells with adverse effect extended even to the fill material. Moreover, choice of fill
`materials is highly restricted either due to their specific chemical structure, physical state or hygroscopicity. Additional reports of unpredictable
`disintegration and dissolution of filled hard gelatin capsules in experimental studies have prompted the search for a better alternative capsule shell
`material. The present review aims to provide an overview on the physicochemical, pharmaceutical and biopharmaceutical properties of
`hydroxypropyl methylcellulose (HPMC) as capsule shell material and perform comparative evaluation of HPMC and gelatin in terms of in vitro/in
`vivo performance and storage stability. HPMC capsule provides a highly flexible and widely acceptable platform capable of solving numerous
`challenges currently facing the pharmaceutical and nutraceutical industries and expands the possibilities for selection of different types of fill
`materials. The current topic introduces a new section on influence of various factors on in vitro dissolution of HPMC capsules. Delayed in vitro
`disintegration/dissolution of HPMC capsules in aqueous medium does not produce any negative effect in vivo. However, advancements in the
`processes of production and filling of HPMC capsule shells and detailed studies on effects of various parameters on their in vitro/in vivo dissolution
`would establish their supremacy over hard gelatin capsules in future.
`
`Keywords: Gelatin, HPMC, Formaldehyde challenge test, In vitro dissolution, Stability study
`
`© 2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
`DOI: http://dx.doi.org/10.22159/ijpps.2017v9i10.20707
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`
`
`INTRODUCTION
`
`Capsule, a versatile unit solid dosage form for oral administration is
`designed to enclose solid, liquid or semi-solid mixture of active
`pharmaceutical ingredient (API) and suitable excipients in hard
`gelatin shells or in soft shells of gelatin [1]. Capsule-based time
`controlled pulsatile drug delivery system has been designed and has
`ushered a new era in chronotherapeutics for synchronisation of drug
`delivery in management of diseases with circadian rhythm [2].
`Capsules are capable of providing protection to encapsulated drug
`from deterioration induced by atmospheric oxygen, light, moisture
`etc. owing to the barrier effects of shell [3].
`
`Gelatin is the most widely used capsule shell material because of its
`non-toxicity, solubility in biological fluids at body temperature,
`ability to undergo thermal gelation and form a strong, flexible and
`homogeneous film [4]. Gelatin is widely used for stabilisation of
`pharmaceutical suspensions and also in design of novel drug
`delivery systems such as wafers [5, 6]. However, few inherent
`characteristics of gelatin responsible for compromised in vitro
`stability of capsule and somewhat unpredictable disintegration and
`dissolution in experimental studies have given rise to the need for a
`better alternative for capsule shell material. Problems associated
`with selection and performance of gelatin are mentioned below.
`
`excipient-excipient interaction, formation of insoluble skin or pellicle
`on the gelatin shell and ultimately retarded dissolution [9]. A well
`known example of excipient-induced cross-linking of gelatin is that
`due to formaldehyde produced as a result of the decomposition of
`lactose. Environmental
`factors such as high humidity, high
`temperature and UV light can also induce cross-linking reactions [8].
`
`Moisture content and stability problem
`
`Water (13%w/w to 16%w/w) in the gelatin film acts as a plasticiser
`and enables the formation of a tough but flexible film. Change in
`relative humidity of the environment may either lead to brittle or
`soggy shells with sometimes a negative impact on the fill material [3,
`4, 9, 10]. Sensitivity of gelatin to extremes of humidity is the major
`area of concern for use of capsules in too humid/dry climates.
`
`Temperature-dependent disintegration/dissolution
`
`Temperature is a key parameter that should be strictly controlled
`during disintegration and dissolution testing of capsules. Problem
`arises when temperature falls below 37 °C, since gelatin solubility
`decreases. At temperature below 30 °C, the capsule shells are
`insoluble and simply absorb water, swell and distort. Because of this,
`compendia and Pharmacopoeia of different countries have set a limit
`of 37 °C±1 °C for carrying out these tests on capsules [3, 11].
`
`Cross linking
`
`Religious perspective
`
`Since, gelatin is a naturally occurring protein, it is susceptible to
`hydrolysis producing amino acids. Therefore, it can be reactive
`towards molecules of varying chemical structures mainly aldehydes or
`any formulation component possessing aldehydic functional group,
`reducing sugars, metal ions, plasticizers and preservatives. The
`amphoteric nature of gelatin may lead to incompatibility with anionic
`and cationic polymeric excipients as well as surfactants [7, 8]. Some of
`the commonly used excipients in preparation of various dosage forms
`such as fats, polyethylene glycol and its ethers, aliphatic alcohols or
`phenols, polysorbates and esters of unsaturated fatty acids can
`undergo auto-oxidation to form aldehydes. The aldehydic end–
`products of degradation can cross-link with gelatin resulting in
`
`The animal source of gelatin is an area of concern for some sections
`of population such as vegetarians or vegans and people belonging to
`certain religious or ethnic groups who practice diets that forbid the
`use of animal products [12].
`
`Special manufacturing conditions
`
`Liquid and semi solid filling cannot be done in hard gelatin capsules.
`Although, soft gelatin capsules provide a better alternative for such
`fill materials, special manufacturing conditions and stringent
`environmental control of temperature and humidity are required for
`their production. During the process of capsulation, the temperature
`and humidity of the air are maintained at 57-59 °F and 20% RH.
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`Drying needs to be carried out in an environment corresponding to
`25
`°F. Typical environmental conditions
`for soft capsule
`manufacturing include 78 °F and 15% RH or 68 °F and 20% RH [13].
`
`The above-mentioned shortcomings and pitfalls of gelatin as capsule
`shell have driven the development of alternative shell-forming
`materials. Extensive literature review results in few studies on
`capsule shells made of Hydroxypropyl methylcellulose (HPMC) and
`also provides names of suppliers of empty HPMC capsule shells in
`international market. No single study carried out till date can throw
`light on the various criteria that are fulfilled by HPMC as alternative
`capsule shell material and its comparison to gelatin. Although
`indications about the in vitro and in vivo performance of HPMC
`capsules could be found, studies on compatibility of HPMC with
`various excipients and fill materials, data on the effect of different
`parameters on dissolution of empty and filled HPMC capsules are
`lacking. The present review has been designed to bridge these
`existing gaps in comprehensive knowledge about HPMC as capsule
`shell material.
`
`HPMC as an alternative capsule shell material
`
`Selection of capsule shell material alternative to gelatine should start
`with a discussion on few essential criteria to be fulfilled by the
`material of choice. The alternative capsule shell material should be
`preferably of plant origin, should not undergo cross-linking
`reactions with various excipients, should be stable towards
`fluctuation of environmental temperature and humidity during
`production and storage, should not exhibit temperature-dependent
`disintegration/dissolution and should be able to contain any fill
`material. Commercial-scale manufacturing needs a capsule with
`gelatin-like performance that can run on existing filling equipment.
`Regulatory bodies will accept a polymer for capsule that has a
`proven safety record and wide regulatory acceptance. Clinicians ask
`for an alternative from which patient compliance is assured with
`comparative therapeutic efficacy as that of gelatin [14].
`
`Recently, a research study has been reported with hard alginate
`capsule shell incorporating amoxicillin in the development of
`gastroretentive floating drug delivery system [15]. HPMC, also
`known as Hypromellose seems to fulfil the desirable criteria of an
`alternative shell material. It is produced by synthetic modification of
`the renewable, plant resource, cellulose obtained from either pine or
`poplar [12]. Chemically, it is a methyl and hydroxypropyl mixed
`ether of cellulose [16].
`
`HPMC is available in different grades (E series, K series) with limits
`on methoxy and hydroxypropyl groups which
`influence the
`properties such as gelation temperature, viscosity, flexibility and
`hydration [14]. HPMC is very popular in fabrication of oral
`controlled release drug delivery systems, microsponges and in
`coating of conventional capsules for achieving sustained drug
`release profile [17-19].
`
`Some of the physicochemical and pharmaceutical properties of
`HPMC that make it the most suitable and preferable alternative
`material to gelatin as material of construction for capsule shell are-
`
`a.
`
`It is semi-synthetic in nature, derived from plant cellulose,
`
`b. Cross-linking problem with the excipients is totally absent since,
`the polymer is free from amino acids,
`
`c. Can be used for a variety of fill materials containing aldehydic group,
`
`d.
`It readily dissolves in cold water giving a colloidal solution
`owing to the reversible thermal gelation property,
`
`e. Forms a flexible film of controlled dimensions,
`
`f. Water does not act as a plasticiser for HPMC. Hence, it has better
`stability at different
`temperature and moisture conditions,
`compared to gelatin. It has been reported that Quali-V® capsules
`from Shionogi Qualicaps with 4-6% moisture content are made from
`hypromellose and are stable at low humidity conditions during
`storage or when filled with hygroscopic formulations. They can be
`dried to<1% moisture content without being brittle. It has been seen
`that the rate at which water diffuses through Quali-V® capsule films
`
`is about half of the rate for Qualicaps® made of gelatin. This
`indicates that HPMC capsules are more suitable for moisture
`sensitive products. In a brochure on Embo Caps VG, it has been
`reported that their capsules are resistant to breakage during
`processing, transportation and are also more stable at moisture
`levels of 3-5% [20-22],
`
`g.
`Its non-ionic nature makes it compatible with most of the
`commonly used excipients as well as APIs,
`
`h. Does
`Spongiform
`TSE(Transmissible
`require
`not
`Encephalopathy) certification and hence time necessary
`for
`documentation and regulatory filings is reduced[16],
`
`i. Adhesion property, optimum shell texture of HPMC film
`facilitates application of modified release uniform coating with
`excellent performance characteristics,
`
`j. HPMC capsules are easy to swallow as gelatin based ones,
`
`k. HPMC complies with USP/NF, EP and JP standards, and is
`permitted as a food additive for human consumption in accordance
`with 21 CFR 172.874 and Regulation (EC) No 1333/2008. It is
`included in the US FDA Inactive Ingredients Database, and is
`generally recognized as a non-toxic and non-irritant material. It is
`Kosher and Halal certified by Kosher and IFANCA respectively,
`approved for vegetarians by Vegetarian Society. It is globally
`available and accepted since it is manufactured in facilities which are
`ISO 9001 certified
`in compliance with IPEC’s (International
`Pharmaceutical Excipient Council) Good Manufacturing Practice
`(GMP) Guide for Bulk Pharmaceutical Excipients [12,16, 23],
`
`l. Non-GMO,
`
`m. Preservative-free, allergen-free, starch-free and gluten-free,
`
`n. Eligible for organic label language (EU), suitable for use with
`organic ingredients,
`
`o. Different types of printing can be done such as axial, radial
`(spin), rectified axial and double-printing. Logo can be printed with
`approved inks, can be packaged in suitable materials and post-
`manufacturing treatments such as spraying of lubricants can be
`done. Laser technology can be used as anti-counterfeit strategy,
`
`p. Can be coloured easily with globally approved iron pigments,
`titanium dioxide, caramel, riboflavin, carmine, sodium copper
`chlorphyllin [22] and
`
`q. Dissolution performance is similar to gelatin capsule in terms of
`fast release of drug.
`
`Special manufacturing conditions for production of empty
`HPMC capsule shells
`
`The general manufacturing scheme for the production of HPMC empty
`capsule shells involves mixing of polymer with only water and approved
`colorants/opacifiers as needed, dipping of mould pins in temperature-
`controlled solution of the shell material, drying, positioning and.
`stripping. After the formation of the cap and body of the capsule, the
`empty shell is available for filling of mixture of drug and excipients in
`suitable form and finally the filled capsules are to be polished and sealed.
`Coating and banding may be carried out depending on the bioavailability
`requirement or commercial purpose [24].
`
`In the next section, special emphasis has been put on intermediate
`steps during manufacturing of HPMC capsule shells where they are
`either different from those of gelatin capsules in terms of processing
`conditions or where the need arises for an additional excipient to
`improve stability of HPMC capsule shell.
`
`Gelation
`
`Gelatin capsules are formed by sol-gel transformation at low
`temperature thereby producing a homogeneous film [10]. It is said
`to undergo cold-set gelation, where cooling results in enthalpically-
`stabilized inter-chain helix to form segments of individual chains
`leading to a three dimensional network. On the other hand, aqueous
`solution of methyl and hydroxypropyl methylcellulose are known to
`gel upon heating i.e., heat-set gelation [25]. These gels are
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`completely reversible in that they are formed upon heating yet will
`liquefy upon cooling. The precipitation temperature, gelation
`temperature, and gel strength of these methylcellulose solutions
`were determined as a function of molecular weight, degree of methyl
`and hydroxypropyl substitution, concentration, and presence of
`additives. The precipitation temperature of these polymer solutions
`decreases initially with increasing concentration until a critical
`concentration is reached above which the precipitation temperature
`is little affected by concentration changes. The incipient gelation
`temperature decreases linearly with concentration. The strength of
`these gels is time dependent, increases with increasing molecular
`weight, decreases with increasing hydroxypropyl substitution, and
`depends on the nature of additives.
`
`Gel promoter
`
`lower mechanical strength of the cellulosic film
`Comparatively
`necessitates the creation of a proper gelling system during manufacture
`of empty HPMC capsule shell. Different natural polymers have been
`investigated as gelling agents till date. Marine polysaccharide,
`carrageenan, mainly kappa and iota varieties, has been shown to induce
`gelation of HPMC at room temperature, in presence of potassium
`chloride. This occurs due to ionotropic gelation of carrageenan in
`presence of potassium ion, where carrageenan and potassium chloride
`act as network former and gelling agent/gel promoter [26]. This
`particular gelling system enables the use of existing conventional gelatin
`capsule manufacturing equipments for HPMC capsules [7, 10]. This
`particular variety of HPMC capsule dissolves in gastric fluid (pH 1.2).
`Similar results have been obtained with another gelling system
`consisting of gellan gum as the gelling agent and either ethylene diamine
`tetra acetic acid (EDTA) or sodium citrate as a gel promoter
`(sequestering agents) [7, 21].
`
`Temperature control
`
`In the manufacturing of hard gelatin capsules, the temperature of the
`dipping pins or moulds should be 22 °C and the gelatin solution
`should be maintained between 45 °C to 55 °C. For manufacturing of
`hard HPMC capsules, the temperature of HPMC gelling solution must
`be at least 70 °C in order to form a film. The temperature of the pins
`is controlled post-dip to avoid liquefaction of the films formed on the
`pins, by using induction heating system for the mould pins.
`Temperature should be kept unaltered till drying out of the films in
`order to retain the shape of the capsule [27]. It is noteworthy to
`mention that moisture control is not an essential criterion for HPMC
`capsule shell production.
`
`Sealing and banding
`
`Sealing of the capsule parts provides protection against leakage of
`the liquid fill material, makes the product tamper-resistant, reduces
`oxygen permeation through the shell, increases stability of the fill
`material and also retains any strong odours generated by the
`product within the shell itself [20]. Banding is a process applied for
`both gelatin and HPMC capsules, where the junction between the
`two parts of the capsule are sealed with the help of a sealing liquid
`and/or by applying a coating on the said junction with a layered
`solid material. Banding of HPMC capsules is done by dissolving
`HPMC powder in binary solvent mixture of ethanol and water at
`room temperature, with > 50% w/w of ethanol. Although high
`ethanol percentage
`facilitates
`faster drying,
`it may cause
`flammability and may precipitate toxic effects due to residual
`vapors. Sealing of patented HPMC capsules has been done with
`ethanol at 50 °C on commercial gelatin capsule shell sealing machine
`with good results where the band did not peel off after 1 w storage
`[28]. However, in order to improve the performance of HPMC
`capsule on high speed filling machine, the capsules are treated with
`a gliding agent on the external surface. This may lead to irregularity
`of the sealing/banding edge [29]. Ethanol-free banding is done with
`HPMC water solution containing small percentage of gelling agent.
`Incorporation of gelling agent increases the band strength, reduces
`tendency for band shrinkage, minimises air bubble formation and
`significantly reduces leakage rate.
`
`The capsules are available in sizes ranging from 00E to 4 and size 9
`for early trials with rodents up to size 00, the largest used in human
`
`medicine [27]. Thus, the empty capsules are being manufactured in
`compliance with GMP and ISO 9002 regulations, without the
`addition of ethylene oxide or sulfites at any stage and they have been
`provided FDA “GRAS” status [12].
`
`The resulting HPMC capsules were found to be of reproducible
`qualities in terms of flawless, shiny appearance, weight uniformity,
`dimensional specifications and exhibited robust performance on
`high speed and semi-automatic filling machines with high output
`rates, low rates of rejection (with fewer than 0.01% defects) and
`blister packaging equipments. All these factors shortened dosage
`form development time and thus economically acceptable for any
`commercial scale production. Moreover, tight and reliable sealing
`was also obtained with liquid-filled modified HPMC capsules leading
`to hermetically sealed one-piece capsules [16].
`
`Effect of fill materials on HPMC capsule shell stability
`
`HPMC capsules can be filled with hygroscopic fill materials without
`affecting their mechanical strength or stability [10].
`
`HPMC capsule becomes standard choice for dry powder inhalers (DPI)
`for two reasons. Since, in this type of formulation the fill amount is very
`less, adverse effects of moisture-sensitivity of APIs and equilibrium
`water content of the capsule shell on the dosage form can be significant.
`Secondly, build-up of static charge (triboelectrification) can increase the
`affinity between dry API and interior of shell leading to incomplete
`delivery of the dose. This problem occurs less with HPMC capsules. For a
`capsule-based DPI, an essential requirement is that the capsule should
`be punctured easily without being broken into fragments which could
`have been inhaled. Since, HPMC can tolerate extreme deviations in
`environmental humidity, it is resistant to breakage and clean puncture is
`produced by the inhaler device without fragmentation and also does not
`shrink when kept at low humidity environment [30-32]. In order to have
`favourable drug delivery from device, the HPMC capsule for inhalation
`usually contains slightly higher percentage of moisture. Residual amount
`of drug in capsule and inhaler device after actuation and particulate drug
`dispersion profile in the pulmonary region depend on the level of surface
`lubricant applied to the mould pins during capsule manufacture as well
`as moisture level [16, 26].
`
`Moreover, it is challenging to fill in liquids inside hard gelatin
`capsules, due to the potential for product-shell interactions [20]. The
`liquid ingredient should be non-solvent for gelatin [4]. But HPMC
`capsule can be filled with liquid fill material without compromising
`stability. HPMC capsule provides a very flexible vehicle for the
`formulator to solve many of the challenges currently facing the
`pharmaceutical and nutraceutical industries and expands the
`possibilities [20].
`
`Oils and lipids or drug solution in lipid phase can be filled in HPMC
`capsules with ease, if they are in liquid state below 35 °C. On the
`other hand, if lipid phase is in solid state at 35 °C, they are
`transformed into semi-solid matrices which are thermo softening
`mixtures or are converted into thixotropic mixtures. Semi-solid
`formulations up to 80 °C can be filled in HPMC capsules [20].
`
`Gelatin capsules turned brown when filled with ascorbic acid. This
`problem did not occur with HPMC capsules containing ascorbic acid,
`even when stored at 40 °C and 75% RH for 2 mo [33].
`
`When salicylic acid was used as a fill material for capsules, maximum
`of 2% degradation was observed with HPMC capsules when stored
`at 25 °C/ 60% RH for 18 mo. Percentage of salicylic acid de-
`composition was higher for gelatin capsules stored under identical
`conditions [30].
`
`Visual inspection and brittleness test were carried out on both
`gelatin and HPMC capsules filled with a wide range of liquid and
`semi-solid excipients after being stored at 45 °C for 1 mo. The
`excipients included in the study were propylene glycol, Polyethylene
`glycol (PEG) 400, labrasol, triacetin, triethyl citrate, medium chain
`triglycerides (MCT), cottonseed oil, soybean oil, sesame oil,
`squalene, PEG 400-water-MCT emulsion and gelucire 44/14. Among
`all the excipients studied, only propylene glycol caused softening of
`both gelatin and HPMC capsules. Gelatin capsules were found to
`break for most of the liquid and semi-solid excipients except
`
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`Int J Pharm Pharm Sci, Vol 9, Issue 10, 1-6
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`labrasol, triacetin, triethyl citrate, squalene and gelucire. Labrasol
`caused deformation and sweating was observed in HPMC capsules
`filled with PEG 400. HPMC capsules passed the brittleness test with
`all of them except with PEG 400 [33].
`
`In another investigation, stability study was carried out on both
`gelatin and HPMC capsules with commonly used solvents,
`
`surfactants and co-surfactants for liquid preparations. Study was
`carried out at 45 °C and 75% RH for 7 w and the capsules were
`visually inspected for shrinkage or swelling as well as leakage of fill
`materials [7]. Comparative effects of various excipients on stability
`of gelatin and HPMC capsules are presented in table 1. Surfactants
`may cause denaturation of gelatin resulting in swelling or shrinkage
`followed by leakage from the enlarged pore size.
`
`
`
`Table 1: Excipent compatibility with capsule shell
`
`Excipient
`
`Function
`
`Solvent
`Solvent
`Co-surfactant
`
`Polyethylene Glycol 400
`Caprylic/capric triglyceride
`Propylene glycol monocaprylate 90%
`(Type II)
`Co-surfactant
`Propylene glycol monolaurate (Type II)
`Mono-and di-glycerides (Imwitor 742®) Co-surfactant
`Mono-and di-glycerides (Capmul
`Co-surfactant
`MCM®)
`Caprylocaproyl Polyoxylglycerides
`Lecithin in caprylic/capric
`triglycerides/alcohol
`Polysorbate 80
`Polyoxyl 35 Castor Oil
`
`Surfactant
`Solvent
`
`Surfactant
`Surfactant
`
`Compatibility with gelatin capsule
`shell
`For 7 w
`For 3 w; leakage occurs after that
`For 4 w; leakage occurs after that
`
`Compatibility with HPMC capsule shell
`
`For 3 w; shrinkage occurs after that
`For 7 w
`Not Compatible; leakage occurs in 1st week
`
`For 3 w; leakage occurs after that
`For 4 w; swelling occurs after that
`For 3 w; swelling occurs after that
`
`For 7 w
`Not Compatible; leakage occurs in 1st week
`For 4 w; leakage occurs after that
`
`For 4 w; swelling occurs after that
`For 7 w
`
`For 4 w; shrinkage occurs after that
`For 3 w; leakage and shrinkage occur
`after that
`
`For 7 w
`For 7 w
`
`For 7 w
`For 7 w
`
`
`
`Quality control tests on HPMC capsule shell
`
`The use of HPMC as an alternative to gelatin as capsule shell material
`can only be confirmed by analysing and comparing the quality
`control parameters of the empty and filled HPMC capsules versus
`hard gelatin capsules. The evaluation of the capsules includes
`physico-mechanical parameters such as mechanical strength, gas
`permeability, physicochemical parameters
`like
`formaldehyde
`challenge test, biopharmaceutical studies including in vitro and in
`vivo disintegration and dissolution tests, oesophageal sticking
`tendency test, animal studies and human bioavailability studies, and
`finally development of in vitro-in vivo correlation. Stability studies
`on HPMC capsules under different conditions of temperature and
`humidity form an integral part of quality control tests.
`
`Parameters mentioned above have been studied by various
`manufacturing companies as well as research laboratories. Only
`those parameters where results for the two types of capsules have
`been found to be significantly different are discussed in the
`following section.
`
`Physico-mechanical and physicochemical parameters
`
`Mechanical strength
`
`As a part of mechanical strength estimation, the burst test or
`breaking-force test is employed for determining % brittleness as a
`function of relative humidity for capsules stored under different
`conditions. Brittleness is directly related to quality, stability,
`consistency and resiliency of capsules and more so for liquid-filled
`hard capsules. During the test, no broken or otherwise compromised
`HPMC capsules were found at 2.5%-50% RH. With gelatin capsules,
`100% of the samples were found to be brittle at 2.5% with no
`breakage at 50% RH [7, 20, 30, 34].
`
`Gas permeability studies
`
`Hard gelatin capsules have demonstrated excellent protection
`against oxygen permeability (3.14cc/m2/day) while HPMC capsules
`offer less protection against oxygen transmission (166 cc/m2/day)
`which is attributed to looser structure of HPMC film as observed in
`SEM studies of film cross-sections [10, 30]. Protection against
`oxidation of sensitive APIs or excipients in HPMC capsules can be
`achieved by including an anti-oxidant in the formulation or by
`packaging in blister package with aluminum foil [33]. HPMC
`capsules offered better protection against moisture-induced
`deterioration of the fill material as demonstrated from moisture
`uptake studies by dynamic vapor sorption method when compared
`
`against gelatin capsules at all relative humidity percentages up to
`40% at 25 °C [35]. Similar results were obtained when the films
`were stored
`in close proximity to calcium chloride
`in an
`environment of 92% RH and 25 °C. Water vapor transmission rates
`were found to be 446 and 263 g/m2/24hr, respectively for gelatin
`and HPMC films [30].
`
`Formaldehyde challenge test
`
`Capsules are first filled with lactose spiked with formaldehyde at 25
`ppm and stored in HDPE bottles at room temperature for 1 w,
`emptied and filled with Acetaminophen USP at a fill weight 380 mg
`(±10 mg). After 1 w storage at room temperature, release of
`Acetaminophen from capsule is observed as per the USP monograph
`for Acetaminophen Capsules. The test concludes that the dissolution
`of Acetaminophen from HPMC capsules shell is unchanged while
`gelatin capsule shell retarded drug release due to cross-linking
`reaction induced by formaldehyde [7].
`
`Biopharmaceutical parameters
`
`In vitro disintegration test
`
`Carrageenan, gel promoter in HPMC capsules caused a delay in
`initial burst of the capsules in aqueous medium at body temperature.
`But, once the capsule has ruptured, comparable release profile was
`obtained as with gelatin capsules. This happened due to slow
`hydration of carrageenan [10]. In the disintegration test, HPMC
`capsules without gelling agent have demonstrated disintegration
`times of less than 10 min, as observed with gelatin capsules [16].
`The disintegration times of green tea extract loaded HPMC capsules,
`without gelling agent, were
`tested
`in acetate buffer and
`demineralised water and were found to be<30 min, satisfying the
`USP limits for herbal formulations. Cations in acetate buffer did not
`have any negative impact on HPMC shell material. However, gelatin
`capsules disintegrated comparatively faster [36]. Disintegration time
`of spiranomycin loaded HPMC capsules in acidic medium (pH 1.2)
`was not altered, even after storage at 60 °C and 75% RH for 10 d.
`However, disintegration time was delayed with spiranomycin
`encapsulated in gelatin capsules [33].
`
`In vitro dissolution test
`
`To assess the effect of HPMC on release of drugs belonging to
`different BCS (Biopharmaceutical Classification System) classes,
`release of BCS Class II (ibuprofen) and Class III (acetaminophen)
`drugs were studied in phosphate buffer with potassium or sodium
`ions. Results obtained were compared with data from gelatin
`
`4
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`Accord Exhibit 1026
`Page 4 of 6
`PGR2023-00043
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`Shuid et al.
`
`Int J Pharm Pharm Sci, Vol 9, Issue 10, 1-6
`
`capsules collected under similar conditions. In neutral potassium
`phosphate buffer medium, ibuprofen release was incomplete and
`highly variable from HPMC capsules compared with the gelatine
`capsules which was attributed to the presence of potassium ions
`(K+) in the dissolution medium. In neutral tribasic sodium phosphate
`buffer (pH 7.2) medium, both HPMC and gelatin capsules showed
`complete and less variable drug release. In neutral tribasic sodium
`phosphate buffer (pH 7.2) medium,
`lag
`time
`in releasing
`acetaminophen was less when sodium ions were present instead of
`potassium ions in phosphate buffer. Gelatin capsules rupture fastest.
`Faster disruption is observed as sodium ions do not efficiently bind
`as potassium ions [36]. Various factors affecting dissolution of HPMC
`capsules are discussed below.
`
`Interaction effect of gelling agent in HPMC capsules and
`dissolution medium components on release profile
`
`Change in ionic composition of the dissolution buffer medium by
`using potassium salt instead of sodium salt, resulted in significant
`delay in release of caffeine from HPMC capsules with carrageenan as
`gelling agent, when studied in acidic medium. Increase in potassium
`ion concentration produced further retardation in drug release,
`leading to non-compliance with acceptable limits of USP. However,
`HPMC capsules developed without gelling agent exhibited drug
`release profile independent of pH of dissolution medium, medium
`components, interaction due to shell material or dietary components
`[16, 37]. HPMC capsules developed with carrageenan as gelling
`agent dissolved in gastric fluid (pH 1.2), whethe