An investigation into polymeric excipient-drug compatibility in solid-liquid formulations
The aim of the investigation was to develop a less empirical way of selecting an appropriate polymeric stabilising agent that would effectively maintain good dispersibility of a given drug substance with known physico-chemical properties. This was achieved by quantifying the adsorption of different polymers onto a range of drug substances from different solvent environments and to establish which physico-chemical properties of the polymers control their adsorption or non-adsorption onto a particular drug. The pharmaceutical actives, two proprietary compounds SB-223412, SB-204269 and loperamide HCl were investigated. The drugs are particulate, with very poor water solubility. The drug particles were examined using SEM. The mean particle size was 1.1, 1.4 and 1.0µm respectively. The polymeric excipients chosen for this investigation were the water-soluble polymers hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), gum arabic (GA), guar gum (GG) and lambda-carrageenan (l-carrageenan). The physico-chemical methods developed in this work help improve the current empirical selection of an appropriate polymer in pre-formulation studies. The methods include an initial bottle test screen. The aim of the screen was to establish which polymers were the most effective in producing stable dispersions of the chosen drug substances. The bottle test screen results showed l-carrageenan and HPMC to be effective stabilisers on SB-223412 and loperamide HCl particles respectively. GA, HPMC and 0.15M NaCl l-carrageenan caused partial dispersion on SB-223412, SB-204269 and loperamide HCl respectively. Stable dispersions were monitored by photon correlation spectroscopy (PCS) for changes in particle size after their preparation and also for up to three months thereafter. Samples remained dispersed at three months. The adsorption characteristics of the stabilising and partially stabilising polymers were quantified by the construction of adsorption isotherms under various conditions of pH and ionic strength. All isotherms were low affinity with a pronounced shoulder region followed by a plateau. Generally all stabilising polymers adsorb to approximately the same amount. Clear differences were seen in the amount adsorbed of partial dispersions. The isotherms provided information regarding how much polymer was required to saturate the surface of a given mass of drug and also some insight into the stabilising mechanism. The combined techniques provided very useful qualitative and quantitative information about the physico-chemical, intermolecular and structural properties of pharmaceutical dispersions in a pre-formulation stage.