INTRODUCTION:

The current environment in the pharmaceutical industry and within the healthcare sector is influenced by the challenge of an appropriate balance between increased compliance requirements with GMP/GDP, regulatory guidance and legal enforcements, versus the use of risk assessment. Quality Risk Management allows process and products, and in some cases personnel, to be better protected, and it can be used to help meet regulatory expectations and meet cost demands, or to seek process efficiencies¹.

Polymorphic forms in the context of pharmaceutical guidance refers to crystalline and amorphous forms as well as solvate and hydrate forms .When a drug substance exists in polymorphic forms, it is said to exhibit polymorphism. In general three different categories of polymorphisms are as below.

1) Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.

2) Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice.

3) Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent, if the incorporated solvent is water, the solvate is commonly known as a hydrate.

Polymorphism, in general, denotes the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Conformational rigid molecules exhibit orientation, or packing, polymorphism. Conformational polymorphism arises when a flexible molecule adopts different conformations in different crystal structures².

Polymorphs can also be classified as enantiotropes or monotropes, depending on whether or not one form can transform reversibly to another³. Enantiotropes are members of a pair of polymorphs whose mutual transition temperature is less than the melting point of the either polymorph. Each enantiotrope has its own temperature range of stability. Monotropes are members of a pair of polymorphs that have no mutual transition temperature. One monotrope is always more stable than the other polymorph under all conditions in which the solid state can exist. The arrangement of molecules in a crystal determines its physical properties and, in some cases, its chemical properties⁴. The physicochemical properties of the solid drug can affect its performance. Thus, an understanding of the crystalline state leads to an understanding of the drug properties, which is crucial for pre-formulation and formulation in the pharmaceutical industry.

Importance of Pharmaceutical Solid Polymorphism:

In early development stages of a new drug substance, relatively little information was available regarding its polymorphic forms, solubility, and other aspects. As the final formulation is developed, changes to the manufacturing process may change the purity profile or physical characteristics of the drug substance and thus cause batch failures and other problems with the finished dosage form⁵.

Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility⁵, dissolution rate, optical and mechanical properties, vapor pressure and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety and efficacy of the drug product⁶. The most thermodynamically stable polymorphic form of a drug substance is often chosen during development based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability. However, a metastable form can be chosen for various reasons, including bioavailability enhancement. Since an ANDA applicant must demonstrate that the generic drug product exhibits adequate stability⁷, its recommend that focus on the potential effect that a polymorphic form can have on drug product stability. Nonetheless, because drug product stability is affected by a multitude of other factors, including formulation, manufacturing process and packaging, it is the stability of the drug product and not stability of the drug substance polymorphic form that should be the most relevant measure of drug quality.

Effect on polymorphism of pharmaceutical processing:

Polymorphic forms of the drug substance can undergo phase conversion when exposed to a range of manufacturing processes, such as drying, milling, micronization, wet granulation, spray-drying and compaction. Exposure to environmental conditions such as humidity and temperature can also induce polymorph conversion. The extent of conversion generally depends on the relative stability of the polymorphs, kinetic barriers to phase conversion, and applied stress⁸. Nonetheless, phase conversion generally is not of serious concern, provided that the conversion occurs consistently, as a part of a validated manufacturing process where critical manufacturing process variables are well understood and controlled and when drug product bioavailability has been demonstrated.

Drug substance polymorphic forms can also exhibit different physical and mechanical properties, including hygroscopicity, particle shape, density, flowability and compactibility, which in turn may affect processing of the drug substance and or manufacturing of the drug product. Since an ANDA applicant should demonstrate that the generic drug product can be manufactured reliably using a validated process, again its recommend that manufacturer pay close attention to polymorphism as it relates to pharmaceutical processing⁷.

The effect of polymorphism on pharmaceutical processing also depends on the formulation and the manufacturing process⁶. For a drug product manufactured by direct compression, the solid-state properties of the active ingredient will likely be critical to the manufacture of the drug product, particularly when it constitutes the bulk of the tablet mass. On the other hand, for a drug product manufactured by wet granulation, the solid-state properties of the active ingredient are often masked by the resultant granulation, and the solid-state properties of the active ingredient are less likely to affect the manufacture of the drug product. In the context of the effect of polymorphism on pharmaceutical processing, what is most relevant is the ability to consistently manufacture a drug product that conforms to applicable in-process controls and release specifications.

The active pharmaceutical ingredient (API) and the excipients in a solid oral dosage form may exist in different crystalline modification or may be amorphous. When a predefined solid phase of a drug substance or crystalline excipient in a solid formulation is subjected to a variety of processing conditions during dosage form manufacturing, many phase transformation may take place including interversion among polymorphs, solvates or hydrates and the amorphous form ⁹.During product development, one must identify both the solid phases and recognize the transitions among them under relevant conditions. The stability relationship between crystalline solid phases often changes depending on the temperature, pressure and relative humidity of the environment. The knowledge of mechanism of phase transformations is very helpful in identifying the potential for such transitions and factors affecting their kinetics. The four mechanisms have been shown in the Table-1. The stability relationship between a pair of polymorphs can be categorized as monotropic or enantiotropic. Monotropy: When a metastable polymorph is there, a polymorphic transition to the stable polymorph during processing can proceed via all four mechanisms. For an enatiotropic system, one polymorph is stable below the transition temperature, while the other is stable above transition temperature. Only one polymorph is stable throughout the temperature range for a monotropic system. Enatiotropy: If the temperature does not reach transition temperature during heating, the system is montropic for practical purpose. However if the temperature is raised above transition temperature, polymorphic transition between the two phases can proceed via any of the four mechanisms.

Differences in the physical and mechanical properties of the various crystal forms of a drug substance also affect scale up and transfer from laboratory quantities and procedures through pilot plant and full production¹⁰ as equipment changes, variations in heating or cooling rates, variations in stirring procedures¹¹, and seeding¹², can also influence the result of a crystallization procedure and the solid form obtained.^{13, 14}

Practices for Characterization of Polymorphs in pharmaceutical industries:

Once a variety of crystalline solids have been produced using a suitable polymorph protocol, it is very important to characterize these by proper techniques so that system can become better defined.^15-17 The list of various analytical techniques for characterization are well known. The most definitive of all these technique is single X-ray diffraction because it directly determines differences in packaging and conformation of molecules. Moreover, intermolecular interactions in the solids are elucidated with atomic resolution providing a wealth of chemical data. The important feature of this technique is that it can rule out pseudopolymorphism. Demonstration of a nonequivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. XRPD can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (e.g. IR, Raman, solid-state nuclear magnetic resonance [ssNMR]) are helpful to further characterize polymorphic forms. Where polymorphism is a concern, the applicants or manufacturers of APIs should demonstrate that a suitable method, capable of distinguishing different polymorphs.

In the generic pharmaceutical industry where we expect that the process for manufacturing products are well with in the place and are being manufactured as pre determined polymorphic specification. In routine, we established generic pharmaceutical industry products are tested for characterization of products for amorphous (Figure-1) and crystalline nature (Figure-2), crystalline products are further characterized for their specific forms as per determined specifications. The present era of characterization of polymorphism is the superseded version of characterization of conventionally used polarized microscopy, which was used for the determination of amorphous and crystalline nature of the products.

There is a renewed interest in polymorph, this is partly due to increased economic pressure faced by pharmaceutical companies and the greater awareness of the effect that polymorphs may have on the bioavailability, manufacturability and stability of the product. This is also reflected in regulatory recommendations with regard to polymorphism appearing in both ‘new drug application’ (NDA) and ‘abbreviated new drug application’ (ANDA) particularly those for solid dosage form. ^18-20

Amorphous materials used to be identified by their conchoidal fracture but this method has been also superseded by X-ray, electron or neutron diffraction. If only a few diffuse reflections appear in the diffraction pattern the material is deemed amorphous (Figure-1). With electron microscopy it is also possible to examine the sample directly by transmission, if it is thin enough or otherwise by making a replica of the surface. In amorphous materials, little texture is evident whereas in crystalline materials the crystallite structure can be clearly seen.

In order to fulfill the polymorph characterization requirements of pharmaceutical regulatory authorities and formulators of drug stances it has become more changeable for API industry to meet the specified requirements of the business counter parts, this challenge has also been exerts by the patented polypormorphic forms of API because its challenge for the researcher to have the different polymorphic form of the obvious one otherwise it will be infringement. The analysis plays an important in characterization of polyporphism. XRPD (X-ray powder diffraction) technique is based on Bragg’s law.

Bragg's Law refers to the simple equation:

nλ = 2d sinΘ

Derived by the English physicists Sir W.H. Bragg and his son Sir W.L. Bragg in 1913 to explain why the cleavage faces of crystals appear to reflect X-ray beams at certain angles of incidence (Θ, λ). The variable d is the distance between atomic layers in a crystal, and the variable lambda is the wavelength of the incident X-ray beam; n is an integer.

The Braggs were awarded the Nobel Prize in physics in 1915 for their work in determining crystal structures beginning with NaCl, ZnS and diamond. Although Bragg's law was used to explain the interference pattern of X-rays scattered by crystals, diffraction has been developed to study the structure of all states of matter with any beam, e.g., ions, electrons, neutrons, and protons with a wavelength similar to the distance between the atomic or molecular structures of interest.

The X-ray radiation most commonly used is that emitted by copper, whose characteristic wavelength for the K radiation is =1.5418Å. When the incident beam strikes a powder sample, diffraction occurs in every possible orientation of 2theta. The diffracted beam detected by detector, which is connected to a chart recorder. In normal use, the counter is set to scan over a range of 2theta values at a constant angular velocity. Routinely, a 2theta range of 5 to 70 degrees is sufficient to cover the most useful part of the powder pattern. The scanning speed of the counter is usually 2theta of 2degrees min^-1 and therefore, about 30 minutes are needed to obtain a trace.

The analytical method for the XRPD of product vary individual to individual it depends upon the product nature, quality and stability studies. A typical method for analysis contains start angle, end angle, step size, time per step, scan speed, number of steps and total time taken for the completion of analysis. The method for the analysis is decided and practiced before starting the analytical method validation. Once the method is validated it has to be followed for the routine analysis.

The analysis report generated by the XRPD machine should acts as a shelf explanatory document and it should have the complete set of standard, if required standard diffractogram should be compared (Figure-3) with test having the all information about the peak whatever found in an individual diffractogram as position (2 theta), Heights (Counts), FWHM (2 theta), d-spacing (A) and relative intensity (% age) as shown in Figure-2. Diffractogram of an individual product acts as a chemical fingerprint for the specified form of that product and confirmed on the basis of these parameters. Good quality authentication practice with respect to predetermined specifications comprises these all the parameters prior to approve the pharmaceutical products. During the XRPD authentication review lot of the problems are faced by reviewers due to insufficient information about the subjected products polymorphism characteristics and its pseudopolymorpic characteristic. At present due to increasing polymorph patent competition and overall good up graded awareness about patent practices has also been tighten the quality specification. We think, there are still some more parametric requirements which have to be incorporated in the polymorphic specification of pharmaceutical products as how much shift in total diffractogrma pattern (Figure-4), how much shift in peak of interest is allowable and what should be diffractogram processing parameters means at which counts it should be processed. In general good documentation practices in order to support the quality authentication process and to convince the regulatory authorities, diffractogram must be retained with batch history of products.

Characterization and understanding of the crystal properties is also important for quality control and regulatory purposes.⁴ Information about the various crystal forms of a drug substance is required by the United States Food and Drug Administration (USFDA) in a New Drug Application and a set of decision trees has been provided to assist in the presentation of data for different crystal forms of a drug substance to the USFDA.⁵ Guidelines have also been set up the International Committee of Harmonization to address the existence of different crystal forms of a drug substance.⁶ Furthermore, the different crystal forms of a drug and processes for preparing them are patentable.^2,3 Among the frequently cited uses for patenting different crystal forms are improved formulation, handling and stability, reduced hygroscopicity, and improved solubility and bioavailability.^2-4

CONCLUSION:

A drug substance may exist in many polymorphic forms, but some forms may be rare and not likely to form desired one, but in reality only a subset of polymorphic forms has the potential to develop under the process conditions used to manufacture the drug substance and drug product. Therefore, only those polymorphs that are likely to form during manufacturing of the drug substance should be manufactured. Most marketed pharmaceuticals consist of molecular crystals. Selection of the most suitable crystalline form of a drug in the initial stages of drug development is crucial to save time and cost associated with the drug development process.

Several regulatory documents and literature reports emphasize issues relevant to the regulation of polymorphism. The concepts and principles outlined in these are applicable for an ANDA. However, certain additional considerations may be applicable in case of ANDAs. Often at the time FDA receives an ANDA a monograph defining certain key attributes of the drug substance and drug product may be available in the Unites States Pharmacopoeia (USP). These public standards play a significant role in the ANDA regulatory review process and in case of polymorphism, when some differences are noted, lead to additional requirements and considerations. This commentary is intended to provide a perspective on polymorphism in pharmaceutical solid in the context of ANDAs. It highlights major considerations for monitoring and controlling drug substance polymorphs and describes a framework for regulatory decisions regarding drug substance "sameness" considering the role and impact of polymorphism in pharmaceutical solids.

More expertise are required for the interpretation of diffractograms, the product stability should also be considered at the product quality authentication, because some products change their polymorphs when stored and may be out of specification (OOS) for the formulator or post production users. The polymorphic history should also be kept in mind at the time of approval of batches beginning from the development phase to commercialization and utilization of end user.

Studies regarding polymorphism should be strengthened in order to guarantee and accelerate the development of new pharmaceuticals, Additional developments in screening methodology will further elevate the polymorphic profile in pharmaceutical industry and intellectual property landscape.

REFERENCE:

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Received on 31.08.2012 Modified on 13.09.2012

Research J. Pharm. and Tech. 5(10): October 2012; Page 1264-1269

Mechanism Phase transition Factors influencing	Solid-state Polymorphic transition Hydration/	Dehydration amorphous
Crystallization/ verification	Environment (Temperature, pressure, relative Humidity etc.)	Presence of crystalline defects,
Particle size and distribution and impurities.	Melt Polymeric transitions, verification Relative rates of nucleation, crystal growth,	Cooling and impurities and excipients
Solution Polymorphic transition Hydration/	Dehydration, amorphous	Crystallization/ verification
Rate of solvent removal, ease of nucleation,	processing conditions, undissolved solids and	Excipients.