Multi-methodological investigation of the variability of the microstructure of HPMC hard capsules
Graphical abstract
Introduction
Due to the advantages offered by HPMC, hard capsules made from plant derived polymer Hydroxy Propyl Methyl Cellulose (HPMC) shells were developed as an alternative to traditional hard gelatin capsules. HPMC shells do not exhibit cross linking reactions, one of the major issues of gelatin, and they contain less moisture than gelatin. They are therefore suitable for hygroscopic actives. Moreover, they are less brittle than gelatin and less susceptible to bacterial growth. Their physical strength tolerates wide ranges of environmental conditions. Thus, these capsules can be used for a broader range of drug products and formulations (Jones, 2004a, Jones, 2004b, Ku et al., 2011, Nagata, 2002, Sherry Ku et al., 2010). Specifically, HPMC enables the incorporation of ingredients that are, hygroscopic, sensitive to moisture or chemically incompatible with gelatin (Stegemann et al., 2015). Moreover, HPMC is a semi-synthetic polymer, with a non-animal origin and therefore is preferred as an alternative for the vegetarian/vegan population (Al-Tabakha, 2010, Karim and Bhat, 2008). This has led to an increased interest in HPMC capsules over past two decades, for both oral and pulmonary dosage delivery (Edwards, 2010, Jones, 2004a, Jones, 2004b, Ku et al., 2011, Nagata, 2002, Nair et al., 2004, Sherry Ku et al., 2010, Stegemann et al., 2014a, Stegemann et al., 2013).
Several types of HPMC capsule shells are now commercially available from dedicated HPMC capsule shell manufacturers (i.e., Capsugel®, Qualicaps®, Suheung®, ACG—associated capsules®, Go Caps®). HMPC capsules mainly differ with respect to the methods of film preparation (Al-Tabakha, 2010, Jones, 2004a). They are either manufactured by addition of a gelling system, using a gelling agent (e.g. carrageenan, gellan gum) and gelling promoter (e.g. potassiumacetate, potassium chloride) to form the capsule shell, or by a thermo-gelation processes without the addition of gelling systems (Al-tabakha et al., 2015, Chiwele et al., 2000).
HPMC capsules require either unique formulations or manufacturing methods, because hypromellose solutions do not undergo a self sol-gelling reaction without process aids. This results in hypromellose capsules from each manufacturer having different properties (Solaiman, 2010). Already subtle changes in manufacturing conditions of the polymeric films, such as gelling temperature, mixing of solution, gelling time, drying temperature/time can have a significant influence on the capsule shell microstructures and physicochemical properties. Thus, the quality attributes of the final products, such as mechanical strength (machinability, handling), in vitro/in vivo behaviour (disintegration/dissolution), stability (oxygen permeability, water vapour permeance), are affected (Al-Tabakha, 2010, Solaiman, 2010). The comprehensive micro-structural interrogation of the relevant physicochemical and physico-mechanical properties of HPMC capsule shells as process/product performance indicators is still rarely performed (Al-tabakha et al., 2015).
The mechanical stability is the key quality attribute of capsules that determines the processability on high-speed filling machines (Stegemann et al., 2014b), which produce up to 250,000 capsules per hour. Current mechanical testing of capsules is limited to traditional methods, which cannot detect micro-structural features of the polymeric films. This results in unique macroscopic mechanical properties and therefore a different machine processability and mechanical strength (Chong et al., 2016, Schoubben et al., 2015). Recently, progress has been made towards the characterization of HPMC capsules, in terms of their puncture behaviour associated with Dry powder inhaler (DPI) product performance (Torrisi et al., 2013). Moreover, several recent works have shown the utility of standard optical microscopy methods to characterize capsule puncture (Chong et al., 2016, Schoubben et al., 2015, Torrisi et al., 2013) in relevance to the efficiency of dry powder delivery. These methodologies together with mechanical characterization are further in progress towards increasing relevance to the product performance.
This study aims towards the thorough physical characterization of different HPMC hard capsule shells using multiple methodologies and eventually derive descriptors, to the best, (semi) quantitatively describe the variation in processability, performance and stability of the product. For this, different approaches were used to obtain information on the microstructural variability of HPMC capsules, derived from different manufacturing processes and/or suppliers. Initially, different dynamic-mechanical analyses were performed for determining mechanical and viscoelastic properties of HPMC capsules. This was achieved using different methodologies, such as transient (static) experiments (tensile properties and creep/creep recovery compliance) and dynamic oscillatory experiments, at different humidity and/or temperature conditions. Secondly, modulated temperature differential scanning calorimetry (mDSC) was performed with different capsule shells, to obtain information on glass transition behaviour, dehydration and enthalpy recovery.
Next, vibrational spectroscopic techniques, such as infrared (IR) and Raman spectroscopy, were used to probe any possible difference in the chemical environment and/or in (inter-) molecular interactions in capsules, obtained via different manufacturing routes. These studies were further supplemented by investigations of the different states (free, bound and total) of water content in capsule shells, as well as thermal dehydration using thermogravimetric analysis (TGA). Finally, a morphological investigation on the capsules was performed using ESEM and OCT methods. The multi-methodological data of HPMC shells was correlated to bulk mechanical strength and a prediction made of the processability. This revealed the microstructural diversity among different HPMC capsule shell batches.
Section snippets
Materials
Three empty, coloured HPMC capsule shells, from different suppliers, and one transparent HPMC capsule were used for the analysis (see Fig. 1). All capsules were stored at ambient conditions prior to analysis. Capsules were identified as A, B, and C. Sample A were chemically-gelled capsules with carrageenan as the gelling agent and potassium chloride as gelling promotor. Sample B were thermally-gelled capsules without any gelling agent. Sample C were chemically gelled capsules with pectin and
Dynamic mechanical and calorimetric characterization of capsule shells
In reference to the diversity of environments that HPMC capsules are exposed to during product manufacturing (filling, packaging etc.) and in the supply chain, it is necessary to estimate the effect of various stressors (e.g., humid atmosphere, temperature, mechanical stress) on the overall quality aspects of oral and inhalation capsule products. Dynamic mechanical analysis provides important information about the thermo-mechanical behaviour of differently manufactured HPMC capsules from
Distinct thermo-mechanical and physicochemical characteristics of different capsule shells
The behaviour of dominantly amorphous polymeric film materials under different static and dynamic mechanical stress states is of relevance in various fields, including packaging, semi-conductors and other industries. In the pharmaceutical sector, understanding the properties of pharmaceutical capsule materials supports the design and manufacturing of capsules, thereby improving processability and performance. Although not clearly noticed in the DSC thermograms, a sub-Tg DMA response – seen for
Conclusion
In this work, we investigated thermal, thermo-mechanical, hygro-mechanical and structural properties of different HPMC capsule shells, using multiple analytical methodologies. Mechanical and thermal analyses led to the understanding that capsules with strongly plasticizing/hygroscopic components, like glycerin (capsule C), are more susceptible to the extraneous stress owing to the reduction in glass transition, as well as an increased tendency of moisture uptake. However, at the same time,
Acknowledgements
Bruker-AXS (Karlsruhe, Germany) is highly acknowledged for providing the Bruker-AXS Microcalix system in this study. Authors thank GSK, UK for providing HPMC capsules from different suppliers. Furthermore we want to thank Mario Hainschitz and Michael Piller for providing their technical support in the lab.
References (52)
- et al.
Hydroxypropyl methylcellulose substituent analysis and rheological properties
Carbohydr. Polym.
(2013) - et al.
Dynamic mechanical thermal analysis of hypromellose 2910 free films
Eur. J. Pharm. Biopharm.
(2011) - et al.
Evaluating the sensitivity, reproducibility and flexibility of a method to test hard shell capsules intended for use in dry powder inhalers
Int. J. Pharm.
(2016) - et al.
Carrier-based dry powder inhalation: impact of carrier modification on capsule filling processability and in vitro aerodynamic performance
Int. J. Pharm.
(2015) - et al.
Pharmaceutical applications of dynamic mechanical thermal analysis
Adv. Drug Deliv. Rev.
(2012) - et al.
An improved X-ray diffraction method for cellulose crystallinity measurement
Carbohydr. Polym.
(2015) - et al.
Gelatin alternatives for the food industry: recent developments, challenges and prospects
Trends Food Sci. Technol.
(2008) - et al.
Performance qualification of a new hypromellose capsule. Part II. Disintegration and dissolution comparison between two types of hypromellose capsules
Int. J. Pharm.
(2011) - et al.
Non-destructive evaluation of polymer coating structures on pharmaceutical pellets using full-field optical coherence tomography
J. Pharm. Sci.
(2014) - et al.
Optical coherence tomography as a novel tool for in-line monitoring of a pharmaceutical film-coating process
Eur. J. Pharm. Sci.
(2014)
Calibration-free in-line monitoring of pellet coating processes via optical coherence tomography
Chem. Eng. Sci.
Hygro-mechanically coupled modelling of creep in wooden structures, Part I: Mechanics
Int. J. Solids Struct.
Powder, capsule and device: an imperative ménage à trois for respirable dry powders
Int. J. Pharm.
Performance qualification of a new hypromellose capsule: part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps Plus, Quali-V and gelatin capsules
Int. J. Pharm.
Modulated differential scanning calorimetry, and glass transition behaviour in poly(methyl methacrylate) and poly(epichlorohydrin) blends
Polymer (Guildf).
Developing and advancing dry powder inhalation towards enhanced therapeutics
Eur. J. Pharm. Sci.
The development of a sensitive methodology to characterise hard shell capsule puncture by dry powder inhaler pins
Int. J. Pharm.
Determination of acetaminophen’s solubility in poly(ethylene oxide) by rheological, thermal and microscopic methods
Int. J. Pharm.
In-vitro tomography and non-destructive imaging at depth of pharmaceutical solid dosage forms
Eur. J. Pharm. Biopharm.
HPMC capsules: current status and future prospects
J. Pharm. Pharm. Sci.
Influence of capsule shell composition on the performance indicators of hypromellose capsule in comparison to hard gelatin capsules
Drug Dev. Ind. Pharm.
The shell dissolution of various empty hard capsules
Chem. Pharm. Bull.
Effect of formulation conditions on hypromellose performance properties in films used for capsules and tablet coatings
AAPS PharmSciTech
Reference database of Raman spectra of pharmaceutical excipients
J. Raman Spectrosc.
Applications of capsule dosing techniques for use in dry powder inhalers
Ther. Deliv.
Comparison of the Gordon-Taylor and Couchman-Karasz equations for prediction of the glass transition temperature of glass solutions of drug and polyvinylpyrrolidone prepared by melt extrusion
Int. J. Pharm. Sci.
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Both authors contributed equally to this work.