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Molecular cocrystals of pharmaceutical interest

Cvetkovski, Aleksandar (2015) Molecular cocrystals of pharmaceutical interest. PhD Thesis , Università degli Studi di Ferrara.

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    Crystal form (cocrystals, polymorphs, salts, hydrates and solvates) assortment remains a scientific challenge that implicates practical issues in the pharmaceutical industry at the late stage of drug development of pharmaceutical formulations and in early stage of synthesis and isolation of an API in favorable defined crystalline form. Indeed, the selection of the optimal crystal form of an API that indisputably impacts the drug development program is directly related to the API’s aqueous solubility. Since the aqueous solubility of an API is the benchmark for its drug delivery and absorption, by crystal form screening, optimization and selection it is possible to control the dissolution rate of API, and thus to determine the extent of its bioavailability and pharmacokinetics profile which are intricately interrelated to solubility and crystal forms. Therefore, understanding the crystal packing forces and their impact upon physicochemical properties of different crystal forms is threshold for controlling the performance of the API. The array of crystal forms in which molecular crystal of API may exist prevails over its possible polymorphs, salts, solvates and hydrates due to the vast number of potential coformers which, not only extend over the limited counterions for salt formation, but also they are much more versatile in nature and thus imply for more complex intermolecular interactions based on different H-bonding with API that lead to conformational changes and flexibility for crystal packing in process of cocrystallization. Molecular crystals of pharmaceutical interest are amenable to excel the phase transition in API which exert polymorphism. But on the other hand, due to the conformational flexibility caused by intermolecular recognition based on hydrogen bonding, they exploit the new polymorphic forms of the API that might be stabilized in the presence of favorable selected coformers. Another benefit of the molecular crystals cocrystalized with appropriate coformers is controlling the stereoselective resolution of the racemic APIs. The concept of modifying the properties of the API by the forming the molecular crystals containing single API in combination with coformer that is another API or functional excipient that improves the performance of the drug delivery or in the formulations, compared to the native API crystal, has become emerging paradigm for drug development programs. Moreover the combination of fixed-doses formulation have been frequently prescribed for therapy, the multi-API or “drug-drug” molecular crystals are relatively unexploited solid forms of APIs. This molecular crystals cocrystallized of the different by nature API, but complementary in terms of pharmacological effect or their mechanism of action have potential relevance for improving the physicochemical properties of both APIs, their biopharmaceutical performance and synergy in pharmacological respond. Crystal form screening of metformin yields two groups of molecular salts. The one comprises the molecular salts of metformin with a wide range of organic acids recognized as safe for food additives, the other is referred to molecular salts of metformin cocrystallized with coformers which are APIs (diclofenac, dichloroacetic acid, glycolic acid, and salicylic acid) and functional excipients (saccharin and acesulfame). Preliminary testing of cytotoxicity of the molecular crystals of metformin with dicloroacetic acid indicate an increased anticancer effect comparing to the effect exerted by the native drugs. .

    Item Type:Thesis (PhD Thesis)
    Date:14 April 2015
    Tutor:Gilli, Paola
    Coordinator:Bignozzi, Carlo Alberto
    Institution:Università degli Studi di Ferrara
    Divisions:Dipartimento > Scienze chimiche e farmaceutiche
    Subjects:Area 03 - Scienze chimiche > CHIM/02 Chimica fisica
    Uncontrolled Keywords:Pharmaceutical cocrystals, Metformin, Hydrogen bond, Crystal structure determination, X-ray crystallography, Cocristalli farmaceutici, Metformina, Legame ad idrogeno, Determinazione della struttura cristallina molecolare, Cristallografia a raggi-X
    Deposited on:30 Jul 2015 08:33


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