Hydroxypropyl methylcellulose, HPMC, is a water-soluble hydrophilic, non-ionic cellulose ether that gels, is stable over the pH range 3.0–11.0 and is enzyme resistant.It is composed of alternating carbohydrate-units joined together by β-1,4 linkages (Fig.1). HPMC has grown in interest in recent years for its use as an excipient, as it’s able to survive harsh digestive environments and processes as well as the ability to release an API into the bloodstream in a controlled manner. However, due to the lack of knowledge in understanding the relationship of the synthesis process and the resulting structure, there is batch inconsistency and the products often show different properties e.g. in clouding point, or drug release profiles when used in tablet coatings. Polymeric excipients such as HPMC are especially problematic because investigating the properties of polymers at the molecular level is non-trivial thanks to their high molecular weight.

The methodology proposed herein (Scheme.1) employs the use of cellobiose, which is a dimer of the cellulose backbone, to synthesise and study small molecular analogues of long chain polymeric excipients. The use of low molecular weight analogues increases the ability to extrapolate information on the polymeric derivatives via molecular crystal data via SCXRD analysis. The main angles of interest include tau, phi, psi and omega. The resulting HPMC analogues will act as model excipients to: study the interactions of APIs with carbohydrates, increase the solubility of large non-polar APIs (via cocrystallisation), which in turn will increase the bioavailability of said API, and to improve the drug-release profile.

Strucutre of HPMC

Fully proposed mechanism to HPMC analogues

Keith O'Shaughnessy

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