Slow drug release from HPMC matrix

Dr Ali R. Rajabi-Siahboomi from Colorcon discusses the use of cellulose ether as an excipient in slow release hydrophilic matrix systems

The most widely utilised polymeric carriers in slow release hydrophilic matrices continue to be cellulose ethers¹, with over 50% of current solid dose slow release formulations in the European market using hydroxypropylmethylcellulose (HPMC).

A general structure of a cellulose ether is shown, where the R-group can be a single or a combination of substituents. Properties such as solubility, surface activity, thermoplasticity, film characteristics, thermal gelation and biodegradation are dependent on the chemical nature, quantity and distribution of the substituent groups. These properties make cellulose ethers suitable for use in a wide spectrum of applications in the pharmaceutical industry.

Each anhydroglucose ring of the cellulose contains three hydroxyl groups available for substitution, but the relative availabilities of these groups for etherification are not identical². Thus not all of the hydroxyl groups will take part in the etherification reactions and, therefore, the degree of substitution (DS) is defined as the number of hydroxyl groups per monosaccharide unit that have been etherified. The maximum value of DS is three. The solubility may not simply be assumed to arise due to the hydrophilic nature of the groups introduced, as the hydroxyls replaced were just as hydrophilic.

There are four commonly used non-ionic methylated derivatives of cellulose ethers, each of different substitution levels which may be described as follows:

Methocel A, E, F and K premium types (pharmaceutical grades) are manufactured by the Dow Chemical Company and distributed worldwide (except in North America and Japan) by Colorcon. The chemical substitution of these cellulose ethers are summarised in table 1.

When etherified, water soluble cellulose ethers are also graded based on their viscosity in a 2% w/v aqueous solution at 20°C. For example, Dow has graded its Methocel products based on the above: Methocel K4M and Methocel K15M are HPMC K series (HPMC 2208) and their 2% w/v aqueous solutions, at 20°C, produce viscosities of 4,000 cPs and 15,000 cPs, respectively.

drug release

When HPMC polymers in their matrices are exposed to an aqueous medium they undergo rapid hydration and chain relaxation to form a viscous gelatinous layer, which is commonly termed the gel layer, at the surfaces of the tablet.³ Failure to generate a uniform and coherent gel may cause a rapid drug release. It is the subsequent physicochemical characteristics of this gel layer that controls water uptake and the drug release mechanism from the matrix.

Gel growth occurs as water permeates through the gel layer to hydrate polymer particles immediately beneath the gel, increasing the thickness of the gel layer. Concomitantly the outer layer becomes fully hydrated, erodes and dissolves and water continues to penetrate towards the core of the tablet, at a controlled rate, until the tablet has dissolved.

Although a rapid burst release of soluble drugs from the external layer may occur, drug release is controlled either by diffusion of the drugs through the gel layer or by gradual erosion of the gel exposing fresh surfaces containing drug to the dissolution medium.

Diffusion is the dominant mechanism controlling the dissolution of water soluble drugs and erosion of the matrix is the dominant mechanism controlling the release of water insoluble drugs.⁴ However, generally release of drugs will occur through a combination of these two mechanisms.

During water uptake and drug release, the gel layer will contain polymer, drug and excipients experiencing different degrees of hydration or solution. Scanning electron microscopy (SEM) and NMR imaging have shown that the gel layer structure of HPMC matrices is rather complex and non-homogenous.⁵ Gas bubbles in the layer affect drug release and arise from the compressed air within the dry core.⁶

The relaxation and swelling characteristics of HPMC matrices may influence drug release kinetics.⁷ These matrices have been shown to expand predominantly in an axial direction, which was attributed to equal contribution of gel growth and core expansion in this direction.⁸ The axial expansion of the core was postulated to be due to uniaxial stress relaxation of compression forces in the core as hydration proceeded.⁹

NMR imaging studies have revealed that there is a water mobility gradient across the gel layer of HPMC matrices.¹⁰ This supports previous studies, which show different degrees of polymer hydration at different depths within the gel. When HPMCs with different substitution levels were examined, water mobility values were lower across the gel layer for a Methocel K4M matrix than Methocel E4M or Methocel F4M, although all produced gel layers of the same thickness.¹⁰

formulation criteria

Although interactions between water, polymer, excipient and drug are the main factors determining drug release, formulation variables such as drug and polymer levels and types, drug:polymer:excipient ratios and polymer and drug particle size have been reported to influence rate of drug release from HPMC matrices.¹¹ It is vitally important to have an appreciation of these parameters prior to the formulation of these matrices.

Hydration of HPMC polymers is not affected by natural variation in the pH throughout the gastrointestinal tract. They hydrate rapidly to form a gel layer in the acid conditions of the stomach. However pH of the dissolution fluid has been reported to affect drug release rate.¹² These effects are primarily due to pH influence on the solubility of the drug, which in turn may affect the mechanism of drug release from HPMC matrices.