Mechanosynthesis of a Coamorphous Formulation of Creatine with Citric Acid and Humidity-Mediated Transformation into a Cocrystal

Creatine is recognized as a dietary
staple among athletes, with
two supplement formulations currently available on the United States
market: creatine monohydrate and creatine hydrochloride. Creatine
monohydrate has relatively low aqueous solubility, which hampers its
ease of preparation by consumers. Creatine hydrochloride has excellent
aqueous solubility; however, it exhibits a strong acidic taste with
potentially harmful effects on dental health. Herein, we report a
mechanochemical synthesis of a 1:1 coamorphous formulation of creatine
and citric acid, a-CCA. Milling of anhydrous creatine
and anhydrous citric acid yielded a-CCA, which was found
to be structurally stable under dry conditions. Upon exposure to humid
air, a-CCA rapidly converted into a 1:1 cocrystalline
formulation, c-CCA. Correspondingly, milling of creatine
and citric acid, with at least one source present as a monohydrate,
resulted in direct mechanosynthesis of the cocrystal. The crystal
structure was solved and refined from powder X-ray diffraction data,
and the obtained structure solution was evaluated by energy minimization
calculations. Close inspection of the hydrogen-bonding network revealed
the presence of creatine in zwitterionic form and of citric acid as
a neutral molecule. Additionally, the coamorphous solid and the cocrystal
were studied by infrared spectroscopy, differential scanning calorimetry,
and thermogravimetry. The aqueous solubility of the cocrystal (32.0(8)
g/L) was determined to be ∼2.5× higher compared to that
of commercial creatine monohydrate (13.3(6) g/L). The cocrystal formulation
was determined to be ∼10× less acidic compared to commercial
creatine hydrochloride. The simple, efficient, and scalable method
of preparation, the phase-purity and high degree of crystallinity
under ambient conditions, and the increased solubility (compared to
the creatine monohydrate) and decreased acidity (compared to creatine
hydrochloride) render the 1:1 creatine:citric acid cocrystal an improved
and potentially marketable creatine supplement formulation.

肌酸（Creatine）被公认为运动员的主流膳食补充剂，目前美国市场上有两种在售的补充剂剂型：一水肌酸（creatine monohydrate）与盐酸肌酸（creatine hydrochloride）。一水肌酸的水溶性相对较低，这给消费者的配制操作带来了不便。盐酸肌酸虽具备优异的水溶性，但口感呈强酸性，可能对牙齿健康造成潜在危害。本研究报道了肌酸与柠檬酸1:1共无定形制剂（a-CCA）的机械化学合成方法。将无水肌酸与无水柠檬酸进行球磨，可得到a-CCA，该制剂在干燥条件下结构稳定。当暴露于潮湿空气时，a-CCA会快速转化为1:1共结晶制剂c-CCA。相应地，若以至少一种带结晶水的肌酸或柠檬酸为原料进行球磨，则可直接机械合成该共晶体。研究通过粉末X射线衍射（powder X-ray diffraction）数据解析并精修了该共晶体的晶体结构，并通过能量最小化计算对所得结构解进行了验证。对氢键网络的细致分析显示，肌酸以两性离子形式存在，而柠檬酸则为中性分子。此外，研究还通过红外光谱（infrared spectroscopy）、差示扫描量热法（differential scanning calorimetry）与热重分析法（thermogravimetry）对该共无定形固体与共晶体进行了表征。经测定，该共晶体的水溶性为32.0(8) g/L，约为商用一水肌酸（13.3(6) g/L）的2.5倍。该共晶体的酸性强度约为商用盐酸肌酸的1/10。该制备方法简单高效、可规模化，且所得制剂在常温环境下具备相纯度与高结晶度，同时相比一水肌酸溶解度更高、相比盐酸肌酸酸性更低，因此1:1肌酸:柠檬酸共晶体是一款性能更优异、具备市场化潜力的肌酸补充剂剂型。