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Enabling the paradigm of quality by design requires the ability to quantitatively correlate material properties and process variables to measureable product performance attributes. Conventional, quality-by-test methods for determining tablet breaking force and disintegration time usually involve destructive tests, which consume significant amount of time and labor and provide limited information. Recent advances in material characterization, statistical analysis, and machine learning have provided multiple tools that have the potential to develop nondestructive, fast, and accurate approaches in drug product development. In this work, a methodology to predict the breaking force and disintegration time of tablet formulations using nondestructive ultrasonics and machine learning tools was developed. The input variables to the model include intrinsic properties of formulation and extrinsic process variables influencing the tablet during manufacturing. The model has been applied to predict breaking force and disintegration time using small quantities of active pharmaceutical ingredient and prototype formulation designs. The novel approach presented is a step forward toward rational design of a robust drug product based on insight into the performance of common materials during formulation and process development. It may also help expedite drug product development timeline and reduce active pharmaceutical ingredient usage while improving efficiency of the overall process., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Elucidation of the most stable form of an active pharmaceutical ingredient (API) is a critical step in the development process. Polymorph screening for an API with a complex polymorphic profile can present a significant challenge. The presented case illustrates an extensively polymorphic compound with an additional propensity for forming stable solvates. In all, 5 anhydrous forms and 66 solvated forms have been discovered. After early polymorph screening using common techniques yielded mostly solvates and failed to uncover several key anhydrous forms, it became necessary to devise new approaches based on an advanced understanding of crystal structure and conformational relationships between forms. With the aid of this analysis, two screening approaches were devised which targeted high-temperature desolvation as a means to increase conformational populations and enhance overall probability of anhydrous form production. Application of these targeted approaches, comprising over 100 experiments, produced only the known anhydrous forms, without appearance of any new forms. The development of these screens was a critical and alternative approach to circumvent solvation issues associated with more conventional screening methods. The results provided confidence that the current development form was the most stable polymorph, with a low likelihood for the existence of a more-stable anhydrous form.

The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted preferentially with nucleophiles at the 8-position rather than at the reactive 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide (including an amide derived from an amino acid), hydroxamic acid, hydrazide and sulfoximide, azide and diazoacetyl derivatives. The in vivo activity is presented of a range of these compounds against TLX5 lymphoma and L1210 leukemia cell lines.

The in vitro cytotoxicity, stability, and metabolism of the 8-(N,N-dimethylcarboxamide) and 8-(N-methylcarboxamide) analogues of the experimental antitumor drug mitozolomide have been investigated in conjunction with their in vivo murine pharmacokinetics and metabolism. When tested against the TLX5 lymphoma in vitro the ID50 values for dimethylmitozolomide, methylmitozolomide, and mitozolomide were 14.6, 3.0, and 2.3 microM, respectively. The cytotoxicity of dimethylmitozolomide was dramatically increased when it was incubated with murine hepatic microsomes. There was no significant difference in the in vitro stabilities of dimethylmitozolomide and methylmitozolamide with half-lives of 43.5 and 45.8 min, respectively, in RPMI at 37 degrees C. The in vitro microsomal incubation of dimethylmitozolomide produced significant amounts of methylmitozolomide, which suggests that methylmitozolomide contributed to the cytotoxicity of dimethylmitozolomide in the presence of microsomes. The pharmacokinetics of both dimethylmitozolomide and methylmitozolomide, given i.p. at 10 mg/kg, were investigated in CBA/Ca mice bearing the s.c. solid TLX5 lymphoma. Methylmitozolomide was absorbed rapidly with maximum plasma and tumor concentrations of 10.66 mg/liter and 8.01 mg/kg, respectively, achieved 0.17 h following dosing. Dimethylmitozolomide was also rapidly absorbed with maximum plasma and tumor concentrations of 9.34 mg/liter and 5.00 mg/kg, respectively, achieved within 0.18 h of dosing. Following administration of dimethylmitozolomide, methylmitozolomide was found in both plasma and tumor tissue. The plasma and tumor area under the curves of methylmitozolomide were 87.7% and 120.8%, respectively, of those seen when mice were dosed with authentic methylmitozolomide. By comparison of the area under the curves and clearance values, it was demonstrated that 89% of the administered dimethylmitozolomide was metabolized via methylmitozolomide.