Solid state stability polymorphs

High importance Flowability Absolute and bulk densities Compressibility Polymorphism Solubility Solid-state stability Solution stability... 

This serves as an example of the extremes one can go if one tmly wants to better understand the process and the form of the compound in the product. This approach is less important for detecting polymorphic form conversion in the solid state, since polymorphic solubility typically varies by less than a factor of two and tablets at very low strength would generally be classified as a type one by the biopharmaceutical classification system. In addition, polymorphs rarely have pronounced differences in chemical stability. On the other hand, if a compound is somewhat unstable and significant amount of amorphous material is potentially present, this approach can be used to determine if it is responsible for drug instability in the tablet formulation. In any event, this reference serves as a very good example of the strength of a powerful approach that has not been widely applied in our industry. 

The transformation behavior of phenylbutazone polymorphs during grinding at 4 and 35°C, and the solid-state stability and dissolution behavior of the ground materials, was investigated [12]. The a, P, and 5 forms were transformed to the new -form, which in turn was transformed to the (which was stable at 4°C). On the other hand. 

Acquisition of potential compounds This could be achieved by chemical synthesis or by extraction from natural resources. This stage includes the development of analytical methods to confirm identity and purity of the compound, and its stability under real-life and stressed storage conditions. Physicochemical properties of the compound are identified, such as the solid-state form (polymorphism, hydrates, and solvates), melting point, solubility, and stability. Synthesis of the molecule is scaled up as the compound progresses in the development pathway. A formulation suitable for human administration and commercialization is identified and scaled-up. 

Experimental (NMR, X-ray and DSC) and theoretical studies [DFT B3LYP/6-311 + + G (d,p)] by Nieto et al. have permitted to establish the structure of the main tautomeric form of 8-hydroxycarbostyril. " In the gas phase two tautomers, 8-hydroxyquinolin-2(lH)-one and 2,8-quinolinediol show similar stabilities. In solid state two polymorphs of 8-hydro-xyquinolin-2(lH)-one have been isolated and their structures elucidated polymorph A, which crystallizes in orthorhombic space group, and polymorph B, which crystallizes in monoclinic space group. The arrangement of molecules in both structures is characterized by intermolecular N-H... O and 0-H... 0 hydrogen bonds. 

Some early applications and potential benefits of the technique were described by Bolton, Prasad, and co-workers [2-5]. Highlighting an area where Raman spectroscopy currently provides valuable data, these workers showed how the lattice vibrations (or phonons) are of considerable value in the characterization of solid states of a drug and especially for the investigation of polymorphism. In addition to examining solid-state stabilities of crystalline modifications to drug crystals, the value of the technique for researching solute-solvent interactions of pharmaceutical materials was also demonstrated. 

The solid-state properties like crystallinity, polymorphism (crystal structure), shape (morphology), and particle size of drugs are important in the stability, dissolution, and processibility of drugs. Some commonly used methods in solid-state studies include microscopy, hot stage microscopy with polarized light, x-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared FTIR/Raman, and solid-state NMR. 

The physical form of the salt must be taken into account and several issues must be considered (Serajuddin and Pudipeddi, 2002). Forexample, amorphous material might result. Even if crystalline, the salt form might prove to be polymorphic. On crystallization or recrystallization, formation of a hydrate or a solvate might occur, and the effect of temperature and humidity on this form should be investigated. Both the physical and chemical stability of the different candidate salt forms in the solid state will ultimately deLne the optimal form of the drug. 

Other studies have demonstrated that polymorph differences do not always translate into bioavailability differences. Gunning et al. (1976) have published results fordisopyramide, an example of a drug that showed similardissolution rates for both forms (I and II). Bioavailability studies in healthy human volunteers also showed no differences in bioavailability from identical capsule formulations of the two polymorphs. Umeda et al. (1984) reported on the case of benoxaprofen, in which the two forms had no signiLcant differences in bioavailability in rabbits, despite a 1.5 times solubility advantage for form I over form II. Bioavailability differences for solid states need to be veriLed by in vivo studies, and in those cases where there is no advantage, the more stable form should bi developed for stability reasons. 

Polymorphism is customarily monitored by melting point or infrared spectral analysis. However, other methods, such as X-ray diffraction, thermal analytical, and solid-state Raman spectroscopy, also can be used. It is expected that the sponsor will conduct a diligent search by evaluating the drug substance recrystallized from various solvents with different properties. Either the basis for concluding that only one crystalline form exists, or comparative information regarding the respective solubilities, dissolution rates, and physical/chemical stability of each crystalline form should be provided. 

Even though molecular crystal polymorphs contain exactly the same molecules or ions, they usually possess different chemical and physical properties such as density, diffraction pattern, solid-state spectra, melting point, stability and reactivity. 

Since polymorphs yield the same molecules upon transition to a less dense phase (liquid or vapour) and upon dissolution, the possibility of polymorph interconversion brings about the problem of structural nonrigidity in solution and in the solid state [24], Isomerization processes in the solid state are well known and there is the intriguing possibility that less stable conformations are stabilized in the solid state by the packing. 

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