Synthesis and Characterization of an Inclusion Complex of dl-Aminoglutethimide with β-Cyclodextrin and Its Innovative Application in a Biological System: Computational and Experimental Investigations.
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SUBMITTER: Ray S
PROVIDER: S-EPMC8992260 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Risperidone (RSP) is an atypical antipsychotic drug used in treating schizophrenia, behavioral, and psychological symptoms of dementia and irritability associated with autism. The drug substance is practically insoluble in water and exhibits high lipophilicity. It also presents incompatibilities with pharmaceutical excipients such as magnesium stearate, lactose, and cellulose microcrystalline. RSP encapsulation by randomly methylated β-cyclodextrin (RM-β-CD) was performed in order to enhance drug solubility and stability and improve its biopharmaceutical profile. The inclusion complex formation was evaluated using thermal methods, powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR), UV spectroscopy, and saturation solubility studies. The 1:1 stoichiometry ratio and the apparent stability constant of the inclusion complex were determined by means of the phase solubility method. The compatibility between the supramolecular adduct and pharmaceutical excipients starch, anhydrous lactose, magnesium stearate, and cellulose microcrystalline was studied employing thermoanalytical tools (TG-thermogravimetry/DTG-derivative thermogravimetry/HF-heat flow) and spectroscopic techniques (UATR-FTIR, PXRD). The compatibility study reveals that there are no interactions between the supramolecular adduct with starch, magnesium stearate, and cellulose microcrystalline, while incompatibility with anhydrous lactose is observed even under ambient conditions. The supramolecular adduct of RSP with RM-β-CD represents a valuable candidate for further research in developing new formulations with enhanced bioavailability and stability, and the results of this study allow a pertinent selection of three excipients that can be incorporated in solid dosage forms.
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Project description:BackgroundIn this study we investigated the predictability of three thermodynamic quantities related to complex formation. As a model system we chose the host-guest complexes of beta-cyclodextrin (beta-CD) with different guest molecules. A training dataset comprised of 176 beta-CD guest molecules with experimentally determined thermodynamic quantities was taken from the literature. We compared the performance of three different statistical regression methods - principal component regression (PCR), partial least squares regression (PLSR), and support vector machine regression combined with forward feature selection (SVMR/FSS) - with respect to their ability to generate predictive quantitative structure property relationship (QSPR) models for DeltaG degrees, DeltaH degrees and DeltaS degrees on the basis of computed molecular descriptors.ResultsWe found that SVMR/FFS marginally outperforms PLSR and PCR in the prediction of DeltaG degrees, with PLSR performing slightly better than PCR. PLSR and PCR proved to be more stable in a nested cross-validation protocol. Whereas DeltaG degrees can be predicted in good agreement with experimental values, none of the methods led to comparably good predictive models for DeltaH degrees. In using the methods outlined in this study, we found that DeltaS degrees appears almost unpredictable. In order to understand the differences in the ease of predicting the quantities, we performed a detailed analysis. As a result we can show that free energies are less sensitive (than enthalpy or entropy) to the small structural variations of guest molecules. This property, as well as the lower sensitivity of DeltaG degrees to experimental conditions, are possible explanations for its greater predictability.ConclusionThis study shows that the ease of predicting DeltaG degrees cannot be explained by the predictability of either DeltaH degrees or DeltaS degrees. Our analysis suggests that the poor predictability of TDeltaS degrees and, to a lesser extent, DeltaH degrees has to do with a stronger dependence of these quantities on the structural details of the complex and only to a lesser extent on experimental error.
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