Stability Orders of Acetaminophen and Theophylline Co-crystals Determined by Co-crystal Former Exchange Reactions and Their Correlation With In Silico and Thermal Parameters.
The aim of this study was to determine the thermodynamic stability order of co-crystals using co-crystal former exchange reactions and to validate 2 in silico parameters for predicting co-crystal formation. Co-crystal former exchange reactions were performed using acetaminophen (AC) co-crystals of oxalic acid (OX), maleic acid (MA), and theophylline (TH). The addition of TH to an AC-MA co-crystal (AC-MA) afforded AC-TH, suggesting that AC-TH was more stable than AC-MA. The stability order among the other co-crystals was determined in the same manner. The stability order of the AC co-crystals was determined to be AC-TH > AC-MA ≈ AC-OX. Interestingly, the addition of TH to AC-OX afforded TH-OX. The stability order of the TH co-crystals was also determined (OX-TH > AC-TH ≈ MA-TH). Although the stability order of the AC co-crystals was consistent with the differences in their hydrogen bond energy (ΔE), an in silico parameter for predicting co-crystal formation, it showed no relationship to the excess enthalpy (Hex). These results suggest that co-crystal formation can be predicted with greater accuracy using ΔE rather than Hexfor AC co-crystals. The stability orders of the AC and TH co-crystals also correlated well with their melting points and disintegration temperatures.
Asahi Kasei Pharma Corporation, Shizuoka 410-2321, Japan. Electronic address: mukaida.mb@om.asahi-kasei.co.jp.
Makoto
M
Mukaida
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
Haruna
H
Sato
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
Kiyohiko
K
Sugano
Laboratory of Molecular Pharmaceutics and Technology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki-shi, Gunma 370-0033, Japan.
Katsuhide
K
Terada
D000082:Acetaminophen / Q000737:chemistry*; D018712:Analgesics, Non-Narcotic / Q000737:chemistry*; D001993:Bronchodilator Agents / Q000737:chemistry*; D003460:Crystallization / Q000379:methods*; D004355:Drug Stability; D006860:Hydrogen Bonding; D008298:Maleates / Q000737:chemistry; D008958:Models, Molecular; D019815:Oxalic Acid / Q000737:chemistry; D033362:Powder Diffraction / Q000379:methods; D013806:Theophylline / Q000737:chemistry*; D013816:Thermodynamics; D014961:X-Ray Diffraction / Q000379:methods
D018712:Analgesics, Non-Narcotic; D001993:Bronchodilator Agents; D008298:Maleates; D000082:Acetaminophen; C030272:maleic acid; D019815:Oxalic Acid; D013806:Theophylline
co-crystals; crystal engineering; crystal structure; physicochemical; solid state; stability