Development of a Targeted Polymorph Screening Approach for a Complex Polymorphic and Highly Solvating API

Campeta, Anthony M.; Chekal, Brian P.; Abramov, Yuriy A.; Meenan, Paul; Henson, Mark J.; Shi, Bing; Singer, Robert A.; Horspool, Keith R.

doi:10.1002/jps.22230

Cited by 122 publications

(131 citation statements)

References 16 publications

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“…Campeta 25 carried out this study and found that we are in presence of conformational polymorphism. Indeed, if the pyridine group is superposed for each form, the rest of the molecule is not aligned for each polymorph (Fig.…”

Section: C1 Axitinib An Active Pharmaceutical Ingredient (Api)mentioning

confidence: 90%

“…This broad definition allows to cover 72 different forms for axitinib, out of which five are anhydrate forms, and among the remaining 67 solvates, some co-crystals (definition see later in the chapter) are found. 25 Excluding the pseudopolymorphism allowed by the FDA definition, there remain two cases of polymorphism to be considered:…”

Section: A1 ''What Is a Polymorph?''mentioning

confidence: 99%

See 1 more Smart Citation

Polymorphism, what it is and how to identify it: a systematic review

Brog¹,

Chanez²,

Crochet³

et al. 2013

RSC Adv.

185

142

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This review on polymorphism is a personal, non-comprehensive view on the field of polymorphism -a term which is often misused. Indeed, the discussion about polymorphism and related terms is still ongoing in the area of crystal engineering. This is why we felt it timely to look into the historical development of its definition and to delimit it. A short introduction to thermodynamic aspects and characterization methods of polymorphs is given. One chapter is then dedicated to polymorphism of elements and inorganic compounds, before discussing the term for organic and organo-metallic compounds. Chosen examples are given each time to illustrate the cases of polymorphism. In the end, the conclusion yields three flow schemes useful in determining polymorphism for each compound class.

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Section: C1 Axitinib An Active Pharmaceutical Ingredient (Api)mentioning

confidence: 90%

Section: A1 ''What Is a Polymorph?''mentioning

confidence: 99%

Polymorphism, what it is and how to identify it: a systematic review

Brog¹,

Chanez²,

Crochet³

et al. 2013

RSC Adv.

185

142

View full text Add to dashboard Cite

show abstract

“…Because of its strong molecular flexibility, 60 solvates, polymorphs of solvates, and five anhydrous forms have been discovered [106][107][108][109]. The commercial formulation under trade name Inlyta ® contains the stable anhydrous form.…”

Section: Axitinibmentioning

confidence: 99%

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs

2015

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Drugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they can be a challenge to ensure physicochemical stability for the entire shelf life of the drug product. Since clinical failures of polymorph drugs have not been uncommon, and some of them have been entirely unexpected, the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug. In the past, the polymorphism of many drugs was detected fortuitously or through manual time consuming methods; today, drug crystal engineering, in particular, combinatorial chemistry and high-throughput screening, makes it possible to easily and exhaustively identify stable polymorphic and/or hydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related problems or clinical failures. This review describes the concepts involved, provides examples of drugs characterized by poor solubility for which polymorphism has proven important, outlines the state-of-the-art technologies and discusses the pertinent regulations.

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“…1. The resulting [ 14 C]axitinib was mixed with 811 mg of nonradiolabeled axitinib and subjected to polymorph control (crystal form IV) (Campeta et al, 2010), yielding 800 mg of [ 14 C]axitinib drug substance mixture with a specific activity of 7.1 mCi/mmol. The purity of [ 14 C]axitinib drug substance was 99% by high-performance liquid chromatography (HPLC).…”

Section: Chemicalsmentioning

confidence: 99%

Pharmacokinetics, Metabolism, and Excretion of [¹⁴C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

Smith

Pithavala

et al. 2014

Drug Metab Dispos

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The disposition of a single oral dose of 5 mg (100 mCi) of [ 14 C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma T max of 2.2 hours and a geometric mean C max and half-life of 29.2 ng/ml and 10.6 hours, respectively. The plasma total radioactivity-time profile was similar to that of axitinib but the AUC was greater, suggesting the presence of metabolites. The major metabolites in human plasma (0-12 hours), identified as axitinib N-glucuronide (M7) and axitinib sulfoxide (M12), were pharmacologically inactive, and with axitinib comprised 50.4%, 16.2%, and 22.5% of the radioactivity, respectively. In excreta, the majority of radioactivity was recovered in most subjects by 48 hours postdose. The median radioactivity excreted in urine, feces, and total recovery was 22.7%, 37.0%, and 59.7%, respectively. The recovery from feces was variable across subjects (range, 2.5%-60.2%). The metabolites identified in urine were M5 (carboxylic acid), M12 (sulfoxide), M7 (N-glucuronide), M9 (sulfoxide/N-oxide), and M8a (methylhydroxy glucuronide), accounting for 5.7%, 3.5%, 2.6%, 1.7%, and 1.3% of the dose, respectively. The drug-related products identified in feces were unchanged axitinib, M14/15 (mono-oxidation/sulfone), M12a (epoxide), and an unidentified metabolite, comprising 12%, 5.7%, 5.1%, and 5.0% of the dose, respectively. The proposed mechanism to form M5 involved a carbon-carbon bond cleavage via M12a, followed by rearrangement to a ketone intermediate and subsequent Baeyer-Villiger rearrangement, possibly through a peroxide intermediate. In summary, the study characterized axitinib metabolites in circulation and primary elimination pathways of the drug, which were mainly oxidative in nature.

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Development of a Targeted Polymorph Screening Approach for a Complex Polymorphic and Highly Solvating API

Cited by 122 publications

References 16 publications

Polymorphism, what it is and how to identify it: a systematic review

Polymorphism, what it is and how to identify it: a systematic review

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs

Pharmacokinetics, Metabolism, and Excretion of [¹⁴C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

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Development of a Targeted Polymorph Screening Approach for a Complex Polymorphic and Highly Solvating API

Cited by 122 publications

References 16 publications

Polymorphism, what it is and how to identify it: a systematic review

Polymorphism, what it is and how to identify it: a systematic review

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs

Pharmacokinetics, Metabolism, and Excretion of [14C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

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Pharmacokinetics, Metabolism, and Excretion of [¹⁴C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans