Understanding and Managing the Impact of HPMC Variability on Drug Release from Controlled Release Formulations

doi:10.1002/jps.23953

Journal of Pharmaceutical Sciences

Volume 103, Issue 6, June 2014, Pages 1664-1672

https://doi.org/10.1002/jps.23953 Get rights and content

ABSTRACT

The purpose of this study is to identify critical physicochemical properties of hydroxypropyl methylcellulose (HPMC) that impact the dissolution of a controlled release tablet and develop a strategy to mitigate the HPMC lot-to-lot and vendor-to-vendor variability. A screening experiment was performed to evaluate the impacts of methoxy/hydroxypropyl substitutions, and viscosity on drug release. The chemical diversity of HPMC was explored by nuclear magnetic resonance (NMR), and the erosion rate of HPMC was investigated using various dissolution apparatuses. Statistical evaluation suggested that the hydroxypropyl content was the primary factor impacting the drug release. However, the statistical model prediction was not robust. NMR experiments suggested the existence of structural diversity of HPMC between lots and more significantly between vendors. Review of drug release from hydrophilic matrices indicated that erosion is a key aspect for both poorly soluble and soluble drugs. An erosion rate method was then developed, which enabled the establishment of a robust model and a meaningful HPMC specification. The study revealed that the overall substitution level is not the unique parameter that dictates its release-controlling properties. Fundamental principles of polymer chemistry and dissolution mechanisms are important in the development and manufacturing of hydrophilic matrices with consistent dissolution performance. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1664–1672, 2014

Section snippets

INTRODUCTION

Extended-release (ER) dosage forms may provide a number of benefits including reduced dosing frequency, improved efficacy, reduced adverse events, and improved patient compliance, and therefore have competitive advantages over their immediate release counterparts. Among the various types of ER dosage forms, the hydrophilic matrix is the most widely used platform of drug delivery. It is versatile and can accommodate both low and high drug loading, and drug molecules with a wide range of

Materials

Batches of HPMC, substituent grade of USP hypromellose 2208, and viscosity grade of 15,000 mPa s were obtained from Dow (Dow Chemicals, Michigan), Shin-Etsu (Shin-Etsu Chemical Company Ltd., Tokyo, Japan), and Hercules (Hercules Doel BVBA, Doel, Belgium), which are commercially designated as K15M, METOLOSE 90SH-15000, and Benecel^® K15M PH, respectively. Niacin was obtained from Lonza AG (Visp, Switzerland), stearic acid was obtained from PMC Biogenix (Memphis, Tennessee), and Povidone K90D was

RESULTS AND DISCUSSION

Niacin ER tablet is an ER hydrophilic matrix tablet based on HPMC. It has a high drug loading and approximately 16% HPMC. Figure 1 is a control chart of niacin release at 20 h, hereafter designated as D20h, segmented by the HPMC lot used in the manufacture. Although all these HPMC lots were obtained from a single vendor, it is apparent that the drug release was impacted by the lot of HPMC. Some of the tablet lots barely passed the lower specification limit of not less than 75% and several lots

CONCLUSIONS

Variability in the dissolution performance of an ER product was investigated by focusing on a basic understanding of HPMC, the release-controlling excipient. Although the conventional DOEs based on the overall substitution levels, viscosity, and particle size did not fully mitigate the variability, investigations of the structural aspect of HPMC revealed significant chemical and spatial heterogeneity between vendors and potentially within the same vendor. Extensive review of drug release

ACKNOWLEDGMENT

Conflict of interest: This study was funded by AbbVie Inc. AbbVie participated in the study design, research, data collection, analyses, and interpretation of data, as well as writing, reviewing, and approving the publication. All authors are either current or former AbbVie employees and may own AbbVie stock/options.

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Citation Excerpt :
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As one of the most commonly used release-controlling polymers, hydroxypropyl methylcellulose (HPMC) is a polysaccharide decorated with Methoxyl (MeO) and Hydroxypropoxyl (HPO) groups. HPMC has been extensively used to prepare extended-release hydrophilic matrix tablets due to its superior properties, including excellent safety, biodegradability, biocompatibility, high drug-loading capacity, etc (The Dow Chemical Company, Methocel cellulose ethers technical handbook, 2002; The Dow Chemical Company, Using methocel cellulose ethers for controlled release of drugs in hydrophilic matrix systems, 2000; Guiastrennec, Soderlind, Richardson, Peric, & Bergstrand, 2017; Klein et al., 2018; Mohamed et al., 2013; Zhou et al., 2014). HPMC can be classified into different types and grades, which are determined by the MeO and HPO substitution degrees and the molecular weight, respectively.
In this study, we tried to assess the substitute contents of HPMC used in commercial extended-release tablets directly by an innovative Raman imaging-based analysis technique and find their effects on the in vitro performance of these pharmaceuticals. Twenty-seven batches of metformin hydrochloride extended-release tablets from various sources were collected in the Chinese mainland market. While Raman imaging was used to qualitatively analyze the composition of the tablets, the MeO and HPO contents of HPMC were quantitatively assessed by a newly proposed calculation method based on the Raman intensity of corresponding characteristic band. Additionally, the dissolution test was performed to evaluate the relationship between HPMC substitution pattern and in vitro behavior. In sum, our findings indicate that the drug release rate can be downregulated by increasing the MeO content of HPMC, while the high HPO content would largely eliminate the variation of drug release profiles among batches.
Polymeric and lipid-based systems for controlled drug release: An engineering point of view
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Aim of this chapter is to review the most common techniques to produce and to characterize systems for controlled drug release, giving particular emphasis to the fundamentals of the production processes and to the possibility to describe mathematically the phenomena involved in drug release, that is, looking at the processes from an engineering point of view.
The most commonly used materials are briefly reviewed, both the polymeric materials (preformed and ad-hoc synthetized, natural, and synthetic) as well as the lipid materials. Then, the drug delivery systems’ preparation processes are presented and discussed. Particular focus is given to the preparation of micro- and nanoparticles based on preformed polymers, and to preparation processes for liposomes. Advanced characterization techniques for novel and conventional drug delivery systems are then presented. Last but not least, the most modern modeling approaches to describe the drug release from these drug delivery systems are reported and compared.

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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical TechnologyUnderstanding and Managing the Impact of HPMC Variability on Drug Release from Controlled Release Formulations

ABSTRACT

Section snippets

INTRODUCTION

Materials

RESULTS AND DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENT

J Control Release

J Pharm Sci

J Control Release

II. Fickian and anomalous release from swellable devices. J Control Release

J Control Release

J Control Release

J Pharm Sci

Anal Chim Acta

Eur J Pharm Sci

Eur J Pharm Sci

Int J Pharm

Int J Pharm

J Control Release

J Control Release

Using methocel cellulose ethers for controlled release of drugs in hydrophilic matrix systems

Methocel cellulose ethers technical handbook

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Understanding and Managing the Impact of HPMC Variability on Drug Release from Controlled Release Formulations