Drug–Drug Cocrystals Provide Significant Improvements of Drug Properties in Treatment with Progesterone

Abstract

Progesterone (Prog), a natural steroid hormone, is widely used in birth control pills and menopausal hormone replacement therapies. Phloroglucinol (SPF) and resveratrol (RSV) are also two kinds of active products that can be used during pregnancy. Drug–drug cocrystals of Prog with SPF and RSV were designed and successfully synthesized for purpose of bringing improvements of drug properties, including solubility, hydroscopic stability, and color stability. The cocrystals and their hydrate structures were systematically characterized by X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. In addition, powder dissolution experiments of Prog, Prog-SPF, and Prog-RSV were conducted in aqueous solutions with the presence of different surfactants, and the result revealed that the Prog-SPF cocrystal exhibits a superior solubility compared with Prog and Prog-RSV. Furthermore, the Prog-SPF cocrystal also enhances the hydroscopic stability and color stability of SPF. Those findings may provide a promising formulation to overcome some weaknesses of the parent drugs.

Cocrystals of Oxymatrine: Reducing Hygroscopicity and Affecting the Dissolution Rate

“…Salt formation is the most commonly used method for improving the drug properties, and currently cocrystallization has become one of the hottest topics in pharmaceutical engineering . Without a compromise of the chemical construction, cocrystals can modify the melting point, dissolution, thermal stability, permeability, and then bioavailability of the drug. − …”

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications

“…The physical properties of solid-state materials include melting point, hygroscopicity, solubility, hardness, plasticity, elasticity, etc. Cocrystallization is a powerful approach for improving the physical properties and maintaining the physical stability of drug substances 85 , 86 , which may suffer undesired physical transformation during manufacturing and storage. Herein, we will discuss only the melting point and hygroscopicity in this section, and other properties will be discussed in the following sections.…”

“… API Coformer Ref. Furosemide Caffeine Nicotinamide 115 Brexpiprazole Catechol 108 Nifedipine Isonicotinamide 116 Progesterone Phloroglucinol 85 Antiprotozoal tinidazole p -Aminobenzoic acid 117 Salicylic acid 117 Levofloxacin Metacetamol 95 Epalrestat Betaine 104 Linagliptin Ferulic acid 118 Vitamin K3 1-Hydroxy-2-naphthoic acid 114 6-Hydroxy-2-naphthoic acid 114 Sulfamerazine 114 Tranilast Urea 119 Nicotinamide 119 Nitrofurantoin 4-Hydroxybenzoic acid 120 Vitamin D3 Vitamin D2 106

Figure 11 Diagram of the mechanisms by which cocrystals improve the chemical stability of APIs.

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Supramolecular cis-“Bis(Chelation)” of [M(CN)6]3− (M = CrIII, FeIII, CoIII) by Phloroglucinol (H3PG)

“…The current study is dedicated to new d-metallate-based supramolecular synthons that might be of importance in the design of functional molecular platforms in solution and in the solid-state. As a counterpart, we selected phloroglucinol (H 3 PG; 1,3,5trihydroxobenzene), a triangular hydrogen bond donor widely tested in the formation of hydrogen-bonded architectures [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Its resulting functional character is well documented in the context of topological reactivity [24], combinatorial or modular synthetic strategies [25,35], molecular recognition and selective binding [31,34,39], proton disorder [26], drugs fabrication improvement [27], luminescence switching [28], switchable magnetic properties [23], chiral properties and photonic materials [36], and general molecular organization [23,[29][30][31][32][33][34]37,38].…”

“…As a counterpart, we selected phloroglucinol (H 3 PG; 1,3,5trihydroxobenzene), a triangular hydrogen bond donor widely tested in the formation of hydrogen-bonded architectures [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Its resulting functional character is well documented in the context of topological reactivity [24], combinatorial or modular synthetic strategies [25,35], molecular recognition and selective binding [31,34,39], proton disorder [26], drugs fabrication improvement [27], luminescence switching [28], switchable magnetic properties [23], chiral properties and photonic materials [36], and general molecular organization [23,[29][30][31][32][33][34]37,38]. In particular, molecular recognition and selective binding of H 3 PG and other associated resorcinol and naphtalenediol-type co-formers involved various polynuclear d-metal ions clusters serving as the molecular hosts [31,34,[39][40][41][42]…”