Polymorph assessment

Baumann P, Jonzier Percy M, Koeb L, etal. Amitriptyline pharmacokinetics and clinical response II. Metabolic polymorphism assessed by hydroxylation of debrisoquine and mephenytoin. Int Clin Psychopharmacol 1986 1(2) 102-12. 

Polymorph assessment, on the other hand, is part of the system of quality control. It is necessary to make sure that the scale-up from laboratory preparation to industrial production does not introduce variations in crystal form. Polymorph assessment also guarantees that the product conforms to the guidelines of the appropriate regulatory agencies and does not infringe the intellectual property protection that may cover other crystal forms. 

J. Remenar, J. MacPhee, B. Larson, V. Tyagi, J. Ho, D. Mcllroy, M. Hickey, P. Shaw, and O. Almarsson, Salt selection and simultaneous polymorphism assessment via high-throughput crystallization the case of sertraline, Org. Process Res. Dev., 1, 990-996 (2003). 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Lastly, Llerena etal. (2004) compared the CYP2C9 polymorphisms 1, 2, 3, 4, 5, and 6 in Mexican Americans (n = 98) and Spanish subjects (n = 102). Lower frequencies of the variant CYP2C9 2, one of two alleles reported to have altered catalytic activity, were found among the Mexican Americans. Since no phenotypic comparisons were conducted in this study, the clinical implications remain unclear. The authors suggest the need for further studies to assess whether the drug metabolism of medications such as warfarin maybe affected in this population. 

In such cases, the Nogami method can be applied to the early points curve (Fig. 6) and the solubility, S, of the polymorph can be assessed. One of the important aspects of metastable polymorphs in pharmacy is exactly their higher solubility, since the dissolution rate will also be higher [Eq. (7)]. Hence the bioavailability will be increased where this is dissolution rate limited [21]. 

The dilemmas raised by the genetics of the work are also considerable and are discussed elsewhere [4], A major difficulty is the choice of the appropriate genetic polymorphisms to associate to drug response. A statistical conundrum is created by the need to assess multiple variables that are partially related to one another (without a priori knowledge of the exact nature of such interactions) and that contribute to small effects in clinical trials that are highly costly and often cannot be as large as desired. 

Chasman, D. and R.M. Adams, "Predicting the Functional Consequences of Non-Synonymous Single Nucleotide Polymorphisms Structure-Based Assessment of Amino Acid Variation," /. Mol. Biol., 307, 683-706 (2001). 

In the case of human amylin and Afi our understanding of the diversity in amyloid fibril architecture is the result of a recursive process, since the early morphological observations were followed by assessment of the assembly pathway which in turn yielded a better understanding of fibril polymorphism. However, this structural knowledge is secondary compared to the discovery of small oligomers, globular oligomers, and early protofibrils that appear to be extremely cytotoxic (Hartley etal., 1999 Lambert et al, 1998 Walsh et al, 1999). 

N. Jamshidi, S. J. Wiback, and B. 0. Palsson, In silico model driven assessment of the effects of single nucleotide polymorphisms (SNPs) on human red blood cell metabolism. Gen. Res. 12 (11), 1687 1692 (2002). 

Microscopy is used to identify crystal morphology and size, and to assess physical form issues like agglomeration and solvent occlusion. It can be used to observe polymorphic transformations in real time with the addition of a hot stage fitting. 

It is recommended that concentration measurements for this type of modeling work are based on analytical standards of mole or mass fraction, to avoid the conversion error caused by density effects. The excess solid phase should always be characterized by a suitable analytical technique, before and after the equilibrium solubility measurements, to confirm that the polymorphic form is unchanged. It should be noted that the crystal shape (habit) does not always change significantly between different polymorphic forms, and visual assessments can be misleading. 

Anderson DJ, Puttfarcken PS, Jacobs 1, Faltynek C (2000) Assessment of nicotinic acetylcholine receptor-mediated release of [ H]-norepinephrine from rat brain slices using a new 96-well format assay. Neuropharmacology 39 2663-2672 Anney RJ, Olsson CA, Lotfi-Miri M, Patton GC, Williamson R (2004) Nicotine dependence in a prospective population-based study of adolescents the protective role of a functional tyrosine hydroxylase polymorphism. Pharmacogenetics 14 73-81 Auerbach A, Akk G (1998) Desensitization of mouse nicotinic acetylcholine receptor channels. 

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