Foreword

Formulation is important in drug product development, as no compound can be administered to patients before being formulated into a specific dosage form. In the case of solid pharmaceuticals, after oral administration, compounds eluted from the preparation are absorbed from the digestive tract, transferred to the systemic circulation, and distributed to disease sites to exert their pharmacological effects. In order to achieve drug treatment with a formulation that exhibits sufficient efficacy and safety, products of constant quality need to be supplied to the market. Here, in the process of producing solid pharmaceutical products, such as dosage form/prescription development, stability confirmation, setting of quality standards, and quality control, formulation analysis plays a major role.

Current formulation development from raw materials, to initial formulation, to industrialization, has become mainstream for simpler formulation design to shorten development time. Under such circumstances, there is a high possibility that the physical properties of raw materials such as drug substances and additives are directly reflected in the properties of the preparation, and it is essential to control the nature of drug substances with a view to formulation. Even in formulation design based on quality by design, the physical properties of the raw materials lead to the evaluation of critical material attributes for achieving critical quality attributes, which are critically important. For generic drug manufacturers, if a drug substance is not selected carefully, it may lead to delays in development and cost increases due to crystal formation and quality problems. In recent years, drug price reforms have required the use of less expensive drug substances, but when considering the final cost, it is necessary to understand the physical properties of raw materials accurately and select the best ones in terms of business strategy.

This special issue consists of two reviews and five regular articles that introduce physical property evaluation methods related to preformulation, formulation design strategies, and the latest research on physical properties conducted in the development process of low molecular-weight drugs.

The first review article writen by Kenjirou Higashi et al. is Intermolecular Interactions between Drugs and Aminoalkyl Methacrylate Copolymer in Solution to Enhance the Concentration of Poorly Water-Soluble Drugs. The aminoalkyl methacrylate copolymer Eudragit E (EUD-E) has gained attention as a solid dispersion carrier because it efficiently stabilizes drugs in the amorphous state and enhances drug dissolution in water. This review focuses on hydrophilic and hydrophobic interactions between drugs and EUD-E in solution. ¹H-NMR studies using high-resolution magic-angle spinning, nuclear Overhauser effect spectroscopy, diffusion, and relaxation time measurements successfully identified the interaction sites and strengths in aqueous solution. The knowledge discussed in this review will be helpful in designing a solid dispersion formulation with EUD-E.

The second review article titled Modification of Drug Crystallization by Cyclodextrins in Pre-formulation Study is by Fumitoshi Hirayama and his colleagues. Controlling drug crystallization is one of the important issues in preformulation studies. This review focuses on the use of hydrophilic cyclodextrins (CDs) as additives for controlling drug crystallization via a host–guest interaction. For example, 2,6-di-O-methyl-β-CD and 2-hydroxybutyl-β-CD suppressed the solution-mediated transition of drugs, and as a result, metastable forms selectively precipitated in solution. The use of CDs in crystal engineering provides an opportunity not only for the detection of new polymorphs but also for the modification of crystal morphology. An overview of recent progress in the use of CDs in amorphous formulations is also given in this review.

The first regular article reported by Yuichi Tozuka and his colleagues is Preparation of Amorphous Composite Particles of Drugs with Ursodeoxycholic Acid as Preclinical Formulations. Three ursodeoxycholic acid (UDCA)-based amorphous samples composed of nifedipine, indomethacin, and naproxen were formulated and evaluated via solid-state analysis. Compared with polymer-based solid dispersions, UDCA-based amorphous composites can be maintained in an aqueous suspension due to their low hygroscopicity and can be administered to animals as suspended formulations in the preclinical stage.

Measurement of the Water Content in Semi-solid Formulations Used to Treat Pressure Ulcers and Evaluation of Their Water Absorption Characteristics is the title of the second regular article by Toshiro Fukami and his colleagues The water content and water absorption characteristics in semi-solid preparations were measured using near-infrared spectroscopy (NIRS) and the Karl Fischer (KF) method. NIRS was shown to be a useful, simple, nondestructive tool that is more advantageous than the KF method. NIR and KF measurements can be used to choose external skin preparations to control the amount of water.

Yasunori Iwao et al. contributed the third regular article, Crystal Structures of Flavone C-Glycosides from Oolong Tea Leaves: Chafuroside A Dihydrate and Chafuroside B Monohydrate. This is the first crystallographic study of two flavone C-glycosides, chafuroside A and chafuroside B. The asymmetric unit of the chafuroside A crystal consists of one chafuroside A and two water molecules, and that of chafuroside B contains one chafuroside B and one water molecule. The flavone moiety of chafuroside A is curved, whereas the chafuroside B flavone moiety is relatively flat. The structural features might contribute to the differences in their pharmacological activities related to antiinflammation.

The fourth regular article by Reiko Teraoka and her colleagues is Improving the Solid-State Photostability of Furosemide by Its Cocrystal Formation. The photostability of three types of furosemide (FUR) cocrystals was studied under D65 fluorescent lamp irradiation. FUR-nicotinamide was found to be the most photostable cocrystal due to the shift of the solid-state UV/Vis absorption spectrum toward a region of shorter wavelength where emission of the D65 fluorescent lamp is much lower. Cocrystallization could be a novel strategy for formulation design to improve drug photostabilization.

The final regular article, entitled A New Method for Classification of Salts and Cocrystals Using Solid-State UV Spectrophotometry, is based on the results of Akihito Kiguchiya et al. The potential of UV/Vis spectrometry as a classification technique for salts and cocrystals was investigated using indomethacin salt and indomethacin cocrystals. In comparisons of the integration values of UV/Vis absorption spectra of salt and cocrystals with those of the physical mixtures, large and no differences were observed in indomethacin salt and indomethacin cocrystals, respectively. Thus, solid-state UV/Vis absorption spectra can be used as a new technique to classify drug salts and cocrystals.

These reviews and articles show the importance of physical property evaluation research for preformulation and formulation design. We sincerely thank all the authors for their significant contributions to this special issue.