Abstract
The purpose of this study is to confirm the impact of polar functional groups on inter and intra-molecular hydrogen bonding in haloperidol (HP) and droperidol (DP) and, hence, their effects on dissolution using a new approach. To confirm our theory, a new molecule: deshydroxy-haloperidol (DHP) was designed and its synthesis was requested from a contract laboratory. The molecule was then studied and compared to DP and HP. Unlike DHP, both the HP and DP molecules have hydrogen donor groups, therefore, DHP was used to confirm the relative effects of the hydrogen donor group on solubility and crystal packing. The solid dispersions of the three structurally related molecules: HP, DP, and DHP were prepared using PVPK30, and characterized using XRPD and IR. A comparative dissolution study was carried out in aqueous medium. The absence of a hydrogen bonding donor group in DHP resulted in an unexpected increase in its aqueous solubility and dissolution rate from solid dispersion, which is attributed to weaker crystal pack. The increased dissolution rate of HP and DP from solid dispersions is attributed to drug-polymer hydrogen bonding that interferes with the drug-drug intermolecular hydrogen bonding and provides thermodynamic stability of the dispersed drug molecules. The drug-drug intermolecular hydrogen bond is the driving force for precipitation and crystal packing.
Highlights
Solubility and permeability are the most vital properties that determine the bioavailability of drugs upon oral administration, they form the basis of the biopharmaceutical classification system [1]
In thisInwork we studied threethree structurally related on crystal packing versusdispersion solid dispersion stability
The average solubility parameters (δ) of PVPK30, HP, DP and DHP obtained from three different methods (Hansen’s 3D, Van Krevelen and Hoy’s Methods) were calculated and the difference between the solubility parameters of each drug and the polymer were determined
Summary
Solubility and permeability are the most vital properties that determine the bioavailability of drugs upon oral administration, they form the basis of the biopharmaceutical classification system [1]. With the advent of newer technologies and the use of robotics in drug discovery, massive libraries of molecules are synthesized every year, many fail during early stages of pre-formulation due to poor biopharmaceutical properties [2]. Formulation scientists employ various approaches to address this issue. Amorphous drug forms may have multiple-fold higher solubility compared to their crystalline counterparts [3,4]. This approach is challenging, because the amorphous drug form is Molecules 2016, 21, 719; doi:10.3390/molecules21060719 www.mdpi.com/journal/molecules
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