Using singular value decomposition to analyze drug/ß-cyclodextrin mixtures: insights from X-ray powder diffraction patterns.

The article discusses the use of mathematical models and linear algebra to understand the crystalline structures and interconversion pathways of drug complexes with ß-cyclodextrin (ß-CD). It involved the preparation and analysis of mixtures of indomethacin, diclofenac, famotidine, and cimetidine with ß-CD using techniques such as differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and proton nuclear magnetic resonance (1H-NMR). Singular value decomposition (SVD) analysis is used to identify the presence of different polymorphs in the mixtures of these drugs and ß-CD, determine interconversion pathways, and distinguish between different forms. In general, linear algebra or artificial intelligence (AI) is used to approximate the contribution of distinguishable entities to various phenomena. We expected linear algebra to completely reveal all eight entities present in the diffractogram dataset. However, after performing the SVD procedure, we found that only six independent basis functions were extracted, and the entities of the INM α-form and the CIM B-form were not included. It is considered that this is due to that data processing is limited to revealing only six or seven independent factors, as it is a small world. The authors caution that these may not always reproduce or approach reality in complicated real-world situations.

Stabilization of the Metastable α-Form of Indomethacin Induced by the Addition of 2-Hydroxypropyl-ß-Cyclodextrin, Causing Supersaturation (Spring) and Its Sustaining Deployment (Parachute).

The purpose of this study is to find that a small amount of 2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) can produce a parachute effect on indomethacin (INM). From the examination of dissolution curves and concentration after several days, the supersaturation of INM was observed for the mixtures containing HP-ß-CD at a molar ratio ≤ 0.5, and the sustained deployment of supersaturation was found not only in equimolar mixtures but also in mixtures with a shortage of HP-ß-CD. In the solid state, it was compared the physical properties of INM/HP-ß-CD mixtures using two different mixing methods and determined the stoichiometry of INM and HP-ß-CD. Differential scanning calorimetry (DSC) revealed that the polymorphs of INM were converted by HP-ß-CD into an amorphous state. Furthermore, X-ray powder diffraction (XRPD) and DSC-XRPD demonstrated that INM crystals from the INM/HP-ß-CD mixture prepared from an EtOH solution were metastable. In conclusion, these phenomena may be considered the "spring" and "parachute" effects of mixtures with a shortage of HP-ß-CD, as they depended on the presence of the metastable α-form of INM. The addition of 1/3 to 1/20 equivalents of HP-ß-CD to INM enhanced INM solubility.

Relationship Between Phase Solubility Diagrams and Crystalline Structures During Dissolution of Cimetidine/Cyclodextrin Complex Crystals.

Cyclodextrins (CDs) form complex crystals with drugs and improve physicochemical properties of drugs. However, only few reports have summarized relationships between crystal structures of drug/CD and dissolution behavior. In this study, we developed cimetidine (CIM)/CD complex crystals to achieve sustained drug release and investigated the relationship between the dissolution behavior of CIM/CD complexes and their crystal structures. CIM and 3 types of CDs (α-, ß-, and γ-CD) formed a complex crystal when subjected to solvent mixing. The CIM/CD complexes had a highly reduced dissolution rate compared to that of the physical mixture of CIM and CD. ß-CD improved the solubility of CIM, whereas γ-CD decreased its solubility. Based on the phase solubility diagram, CIM and α-, ß-, and γ-CD indicated A-type positive (AP) and AL deviation, and B-type limited solubility (BS) profiles, respectively. In γ-CD, the saturated concentration of CIM decreased owing to the formation of a low-solubility complex with CIM. CIM/α-CD formed cage-type crystals, and CIM/ß-CD and CIM/γ-CD formed channel-type crystals. The dissolution rate constant (k) of CIM/α-CD and CIM/ß-CD were 0.045 and 0.04 h-1, respectively. CIM/γ-CD and CIM/ß-CD displayed channel-type crystals; however, the channel-type crystals of CIM/γ-CD were stabilized by the presence of additional water molecules.