UNDERSTANDING THE STABILITY OF SALTS AND COCRYSTALS IN A DRUG PRODUCT ENVIRONMENT

Abstract

Transition of a drug substance to drug product necessitates the use of excipients and often includes several unit operations.1 A risk associated with processing pharmaceutical solids is their propensity to undergo solid form transformations such as polymorphism and amorphization. Changes in the physical form during drug product manufacture or storage can have an influence on their chemical stability and product performance. The central goal of this thesis work is to mechanistically understand the influence of processing and formulation composition on the stability of pharmaceutical salts and cocrystals.Processing induced lattice disorder was investigated for caffeine-oxalic acid cocrystals. The unmilled cocrystals were stable in presence of excipient and water. However, very short milling times induced sufficient lattice disorder to induce cocrystal dissociation. Quantification of disorder was performed using X-ray diffractometry (XRD). The lattice disorder was proposed to be predominant on the particle surface experiencing shear and hence served to explain the disproportionate influence that low levels of disorder had on the stability of the cocrystals. Cocrystal dissociation was observed to be a water mediated reaction and was influenced by the pH of the microenvironment. Very low levels of lattice disorder, which cannot be characterized using bulk characterization tools such as XRD and thermal analysis, can induce chemical instability and lead to product failure. Disorder induced during processing was also imaging using atomic force microscopy. The second part of the thesis focused on understanding the challenges associated with the formulation development of levothyroxine sodium pentahydrate (LSP). The influence of pharmaceutical processing on the hydration state of LSP was investigated using single crystal and synchrotron X-ray diffractometry, and a novel crystal form of the drug was reported when it undergoes partial dehydration to form levothyroxine sodium monohydrate (LSM). LSM has a higher chemical reactivity than the pentahydrate form. The influence of excipients on the physical and chemical stability of LSP was investigated using synchrotron XRD and high performance liquid chromatography (HPLC). Hygroscopic and acidic excipients can induce dehydration and salt disproportionation of LSP, respectively. Microenvironment pH and excipient hygroscopicity were critical determinants of LSP stability.