In Situ Metastable Form: A Route for the Generation of Hydrate and Anhydrous Forms of Ceritinib

Abstract

Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor used for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). This BCS class IV drug is developed by Novartis and traded under the name Zykadia. To date two forms [Form A (marketed form) and B] of ceritinib are disclosed in international patent application US 2013/0274279 A1. However, the crystal structure and insight into any solid form of this compound are not available in the literature. In order to achieve better physicochemical properties compared to known solid forms of this compound, novel polymorph identification is chosen as one of the challenging paths to address the issue. In our comprehensive polymorph screening, including in silico and experimental investigations, we discovered three novel solid forms of ceritinib. Out of these three solid forms, two are neat (Form 1 and Form 3) and the remaining one is a hydrate (Form 2). All synthesized forms are further characterized by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. It is interesting to note that the discovery of this hydrate is in sync with the prediction done using COSMO-RS theory (COSMOthermX software). The current article includes the first single crystal structure of ceritinib Form 1. All forms (Form 1, 2, and 3) of ceritinib are subjected to physicochemical property evaluation like solubility in buffers with a pH range of 1–7, dissolution, and stability. In aqueous solutions and pH 4.5 (acetate buffer), the solubility of Form 2 and 3 is high compared to Form 1, whereas in 0.1 N HCl and 0.01 N HCl Form 1 has a higher solubility compared to Forms 2 and 3. A six-month stability study indicates that all forms (Forms 1, 2, and 3) are stable in ICH stability conditions like accelerated (40 °C ± 2 °C, 75% RH ± 5% RH), long-term (25 °C ± 2 °C, 60% RH ± 5% RH), and low temperature (2–8 °C) conditions. A thorough polymorph screening protocol, including in silico prediction, single crystal structure, and physicochemical properties of different forms and structure property correlations for ceritinib are enlightened in the current paper.

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

“…This is because RH = 60% and a w = 0.60 are established as border values for microorganisms’ growth [ 98 ]. Regular and accurate testing in the topic is of great importance as only a proper adjustment of RH, a w and temperature parameters allows control of the phase formation process and, as a consequence, delivers a stable product [ 99 ].…”

Improving Solubility of Poorly Soluble Abiraterone Acetate by Cocrystal Design Aided by In Silico Screening

“…particle size of ABI and its cocrystals are found to be in the range of 3.6 ± 1 μm. In vitro powder dissolution studies were conducted in triplicate for ABI, ABI-SA (2:1) cocrystal, ABI-GA (1:1) cocrystal, ABI-4HBA (1:1) cocrystal, and ABI-35DHBA (1:1) cocrystal at pH 1.2 over different time intervals (5,10,20,30,60, and 120 min). The results are briefly explained below and graphically represented in Figure 12.…”

“…Fine tuning the physical and chemical properties of drugs (pharmaceuticals/nutraceuticals) via the cocrystal approach has drawn considerable recent interest in both academic and industrial pharmaceutical circles. − The majority (over 80%) of new chemical entities (NCEs) are estimated to show low solubility and poor bioavailability; hence they pose challenges in delivering into the body using conventional approaches. , To improve such properties (including solubility, stability, dissolution rate, and purity, etc. ), amorphous forms, polymorphs, cocrystals, hydrates or solvates, and salts serve as options. − Among all these options, cocrystallization has its own advantage, because it allows fine-tuning of the physicochemical properties of an API (active pharmaceutical ingredient) without altering its chemical integrity . Thus, presently cocrystals are attractive in the pharmaceutical industry. , …”

Could Drug Availability Be Improved through Shape Modification?

“…According to the Biopharmaceutics Classification System (BCS), DND is a class II antiarrhythmic medication that helps patients with paroxysmal or chronic atrial fibrillation regain normal sinus rhythm, while CRT is a class IV antineoplastic kinase inhibitor used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). The possibility of generating spherical agglomerates of DND and CRT was investigated by modifying the solvent system, bridging agents, and mixing rate [12,13].…”