Polymorphism pharmaceutical manufacturing

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA) (2004, Dec.), Guidance for industry ANDAs Pharmaceutical solid polymorphism chemistry, manufacturing, and controls information, FDA, Rockville, MD. 

FDA(2004).Guidancefor Industry ANDAs Pharmaceutical Solid Polymorphism Chemistry, Manufacturing and Controls Information, CDER, Rockville, MD. 

The application of Raman spectroscopy in primary manufacturing was reviewed by Fevotte [25] who put a special emphasis on crystallisation monitoring. It includes tables of typical applications in crystallisation monitoring and other transient processes, respectively. The author concludes that several open questions such as better calibration procedures, dependence on size distribution and sampling techniques need to be addressed before we will see a wider use of Raman spectroscopy in pharmaceutical manufacturing applications. Yu et al. [26] presented a broader review of crystallisation control including in-line Raman for polymorph monitoring. The authors discuss future developments needed for the respective techniques and point out the potential of Raman spectroscopy for in-line polymorph detection. 

After discovery of the first cases of polymorphism with dramatic differences in biological activity between two forms of the same drug... no pharmaceutical manufacturer could neglect the problem. (Borka 1991)... 

Zhang, G.G. Law, D. Schmitt, E.A. Qiu, Y. Bauer, M. Bauer, J. Spanton, S. Henry, R. Quick, J. Dziki, W. Porter, W. Morris, J. Highleyman, L. Phase transformation considerations during process development and manufacture of solid oral dosage forms [Crystallization and solid state properties of molecules of pharmaceutical interest] Ritonavir an extraordinary example of conformational polymorphism Ritonavir manufacturing problems. Adv. Drug. Deliv. Rev. 2004, 56 (3), 371-390. 

It is of worthy of note that the International Conference on Harmonization (ICH, Guideline Q6A of the October of1999) includes under the heading of polymorphs single entity polymorphs molecular adducts (solvates, hydrates), amorphous forms . The FDA currently requires that pharmaceutical manufacturers investigate the polymorphism of the active ingredients before clinical tests and that polymorphism is continuously monitored during scale-up and production processes [42], The... 

FDA (2007) Guidance for industry ANDAs pharmaceutical sohd polymorphism chemistry, manufacturing, and controls iirformation. http //www.fda.gov/CDER/guidance/7590fnl.pdf... 

A key issue in pharmaceutical manufacturing is the reproducibility of solid-state attributes of the crystalline product. Batch-to-batch variation in the crystal size, habit, polymorphism, or chemical purity could be caused when certain impurities—usually, reaction by-products from the upstream processes—are present in the crystallizing solution. The resulting modification of crystal properties can affect downstream processing and formulation of the final product. Sometimes tailor-made and polymeric additives are used to tune the crystallization process and, hence, crystal properties at the molecular level. For instance, a good crystal habit can facilitate better filtration and separation. A stable (or metastable) polymorph can influence the stability and formulation behavior of the drug product. 

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

Various drugs are known to exist in different polymorphic forms (e.g., cortisone and prednisolone). The rate of conversion from a metastable into the stable form is an important criteria to be considered with respect to the shelf life of a pharmaceutical product. Polymorphic changes have also been observed during the manufacture of steroid suspensions. When steroid powders are subjected to dry heat sterilization, subsequent rehydration of anhydrous steroid in the presence of an aqueous vehicle results in the formation of large, needle-like crystals. A similar effect may be... 

US patent 6,723,728, Polymorphic and other crystalline forms cis-FTC [106], The present invention relates to polymorphic and other crystalline forms of (—)-and ( )-cA-(4-amino-5-fluoro-l-(2-(hydroxymethyl)-l,3-oxathiolan-5-yl)-2(lH)-pyrimidinone, or FTC) [106]. Solid phases of (—)-cz>FTC that were designated as amorphous (—)-FTC, and Forms II and III were found to be distinguishable from Form I by X-ray powder diffraction, thermal analysis properties, and their methods of manufacture. A hydrated crystalline form of ( )-cA-FTC and a dehydrated form of the hydrate, were also disclosed, and can similarly be distinguished from other forms of FTC by X-ray powder diffraction, thermal properties, and their methods of manufacture. These FTC forms can be used in the manufacture of other forms of FTC, or as active ingredients in pharmaceutical compositions. Particularly preferred uses of these forms are in the treatment of HIV or hepatitis B. 

Polymorphism is critically important in the design of new drug API [9] and affects a number of areas. The main impact is to the bioavailability and release profile of a drug substance into the body. This is due to differences in solubility and dissolution rate, between the polymorphs. The chemical and physical stability of the formulated drug substance is also dependent on the polymorphic form. Patented registration of all discovered forms and their manufacturing conditions is an important element in protecting a pharmaceutical companies intellectual property. 

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