Polymorphism: Its application in the development of pharmaceutical dosage form

Polymorphism comes from the Greek words, Polus = many and morph = shape. Polymorphism means existence of substance in more than one form. Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. However, they share one common form once they are in solution form. Polymorphism is very important in those areas of chemical research where full characterization of a material has a pivotal role in determining its ultimate use e.g. in pharmaceutical, pigment, agrochemical, explosive and fine chemical industries.
When polymorphism exists as a result of difference in crystal packing, it is called packing polymorphism. Polymorphism can also result from the existence of different conformers of the same molecule in conformational polymorphism. In pseudo polymorphism the different crystal types are the result of hydration or solvation.

The types of different polymorphic forms are shown below:

Fig: Types of different polymorphic forms
Polymorphs seem to be more common for compounds with: * Low solubility in water * Organic salts * Formation of hydrates for larger molecules * Organic solvates –neutral compounds with larger molecular weights. * Compounds with molecular weight below 350

Pharmaceutical Properties exhibited by Different Polymorphs are given below: * Density * Melting Point, * Hygroscopicity, * Chemical and Physical Stability, * Apparent Solubility and Dissolution, * Bioavailability and Bioequivalence, * Manufacturability.

Characterization of Polymorphs A number of techniques have been used to identify different polymorphic phases of a compound of methods provides a powerful means for identification and isolation of each crystalline modification. * Optical microscopy: It determines the optical properties (birefringence, indices of refraction, interference figure, dispersion color etc) and morphological properties of particles. * Scanning Electron Microscopy: It determines surface topography and type of crystals (Polymorphism and crystal habit) * Hot Stage Microscopy: The polarizing microscope fitted with a hot stage or cold stage is an extremely valuable tool for the characterization of polymorphic or solvate system. * Single Crystal X-ray Diffraction: Single crystal X – ray diffraction provides the most complete information about the solid state. It will give information about the position of molecular groups within the crystal and thus actually defines the differences between the different forms. * Powder X – Ray Diffraction: Crystalline materials in powder form give characteristic X – ray diffraction patterns made up of peaks in certain position and varying intensities. * Differential Scanning Calorimetric (DSC): It measures the heat loss or gain resulting from physical or chemical changes within a sample * Differential Thermal Analysis (DTA): It monitors the difference in temperature existing between a sample and a reference as a function of temperature. It is useful in fusion, boiling, sublimation, vaporization; crystalline structure inversion, solid-solid transition, and water loss generally produce endothermic effects, and exothermic effects. * Thermo gravimetric analysis (TGA): It is a technique that measures changes in weight that occur to a sample as function of temperature over time. * Fourier Transforms Infrared Spectroscopy (FT-IR): It is the identification of the drug present and distinguishing between solvates and anhydrous form then for identifying polymorphs. * Raman Spectroscopy: It is established technique for identifying and differentiating pharmaceutical polymorphs.
Importance of polymorphism in Pharmaceuticals

* Polymorphism has been recognized as an important element of drug development * Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, apparent solubility, dissolution rate, optical, electrical and mechanical properties, vapor pressure, stability, and density. * These properties can have a direct effect the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Polymorphism is very common among pharmaceutical substance and thermodynamic stability of a polymorph can impact pharmaceutical properties such as bioavailability, process ability and manufacturability. * Polymorphic forms possess higher potential energy with respect to the thermodynamically stable or lowest entry forms. * Different polymorphic phase’s exhibit unique physicochemical properties include solubility, dissolution rates which can influence bioavailability. * The ability to isolate, differentiate, and characterize individual polymorphs is a major challenge to the pharmaceutical industry.

Pharmaceutical application of polymorphism * Purification of drugs: Crystallization is used as a purification process. It is used for removing impurities from pharmaceutical products, i.e., recrystallization technique. * Better processing characteristics: Crystallization technique is used to change the micromeritics of drugs such as compressibility and wet ability. * Improved physical stability: Crystalline forms play an important role in product properties such as suspension stability and hardness of a tablet. Using dehydrating materials such as dehydrated alcohol and glycerol, the stability of hygroscopic substances can be enhanced. * Ease of handling: Crystallization facilitates various operations such as transportation and storage. * Better chemical stability: Crystallization increases the stability of drugs. For example amorphous penicillin G is less stable than crystalline salt. Amitryptyline is more stable in crystalline form than in amorphous form. * Improved bioavailability: Some drugs are more effective in their crystalline form. For example, Penicillin G does not dissolve immediately in the gastric fluids. Therefore, its degradation decreases. Hence, bioavailability of penicillin G enhances. * Sustained release: Drug substances with different sizes of crystals can be used in the production of sustained release dosage forms. For example protamines zinc insulin in crystalline form slowly and continuously release insulin from the site of injection for prolonged periods. *
Application of polymorphism in pharmaceutical industry Different dosage forms are prepared in the pharmaceutical industry. Depending on the dosage forms, their polymorphic characteristic varies. 1. Suspensions
In aqueous vehicles-Due to use of a wrong polymorph of a drug, a phase conversion from the metastable to stable polymorph may occur. This produces:

(a) Crystal growth
Results in undesirable particle size distribution. This can produce serious problems with parenteral suspensions where syringibility of the product can become difficult if significant particle growth occurs. Biological availabilities of the drug also can be altered because phase transitions produce drug particles having different solubilities.

(b) Caking
Produce suspensions that cannot be uniformly resuspended by shaking. A good example of suspensions in aqueous vehicle is the cortisone acetate suspension. Cortisone acetate was one of the most difficult polymorphic problems to solve. Macek obtained the first patent on stable non-caking aqueous suspension of cortisone acetate and methods of preparing the same. He described the early attempts to obtain a stable aqueous suspension, where cortisone acetate, in the form of crystals stable in the dry state, was suspended in the aqueous medium and allowed to remain in the medium for a few hours. It was observed that crystal growth of the cortisone acetate invariably occurred with subsequent caking and sedimentation. A physically stable aqueous suspension was obtained by ball-milling cortisone acetate powder as Form 2, and in the aqueous vehicle where a polymorphic phase transition occurred as Form 5. In a later patent, Magerlein described two new polymorphs of cortisone acetate, Form A, which is not stable in the dry state, and Form B, which is stable in the dry state. Both crystal forms when used in aqueous suspensions gave physically stable, non-caking aqueous suspensions. The cause of the growth of crystals of Form 5, in the early suspensions prepared by Macek, is due to greater solubility of Form 2 in the solution phase than Form 5. The concentration of Form 2 is greater in the solution immediately in contact with Form 5 crystals than the solubility of the Form 5. This happens because of the dissolution of more soluble Form 2 into the solution, resulting in a supersaturated solution with respect to Form 5, the stable configuration.

2. Creams
When creams are prepared with the active ingredient suspended in the cream base, use of the wrong polymorph can result in a phase inversion to a more stable phase. As a consequence, crystal growth can occur in the vehicle yielding gritty, cosmetically unacceptable creams or products in which the active ingredient is unevenly distributed.
During the preparation of a topical cream it is necessary to select the correct polymorph of the active ingredient, which when suspended is least susceptible to growth in the cream base. The correct procedure is to choose the polymorphic phase which is least soluble in the cream base. When a metastable phase with high solubility is suspended in the cream base there is a high risk that nucleation of a more stable (less soluble) form will eventually occur. When this happens, the crystal size distribution in the system is altered as the more stable form gradually replaces the metastable phase. The usual consequence of this process is a substantial increase in the mean crystal size of the suspended drug in the formulation. While crystal growth of finely suspended drug particles can occur in the absence of such transformations, serious consideration should be given to the presence of different polymorphic forms when this type of problem is encountered with a formulation.
In certain instances, the use of the most stable polymorph for suspension in liquid or semisolid dosage forms may not be the best procedure. For example, phase conversion may be so slow in certain ointment bases that a more soluble metastable form may be safely used. It is entirely possible the use of a more thermodynamically energetic form of the drug may result in a more efficacious therapeutic formulation.

3. Solutions
One of the first considerations in formulating a solution is to determine the solubility of the drug in its vehicle. If the solubility determination is conducted using a metastable form of the drug and the concentration of the drug in the system exceeds the equilibrium solubility of a less soluble form of the drug, a thermodynamically unstable formulation results. In a sense, this is akin to emulsions which are also thermodynamically unstable systems. Some solutions that are supersaturated with respect to the stable form of the drug may remain in this state for relatively long periods of time. Chance nucleation of the stable form, however, quickly results in crystallization until equilibrium is reached with respect to this form. This is a frequent problem with sparingly water-soluble drugs, such as the steroids, and this phenomenon has been frequently encountered in these laboratories. Flynn has reported an example of this type of problem in the formulation of a parenteral solution of a drug. In this instance, determination of the water solubility of this compound indicated the drug to be adequately soluble for the concentration required in the formulation. Stability studies on the formulation quickly turned up the presence of a precipitate. An investigation of the problem showed the precipitate to consist of a less soluble polymorph of the compound. The problem was solved by formulating the product in a vehicle containing sufficient co-solvent to solubilize the less soluble polymorphic form.

4. Suppositories
The polymorphic changes of a suppository base could result in a product that undergoes a change in its melting characteristics. If the suppository base is of the type that depends on melting at body temperatures to release the active components of the formulations a relatively small change in its melting point could have severe consequences. If the melting point is depressed the product may melt or soften at shelf temperatures. If the melting point becomes greater than anticipated, the suppository may not melt properly when administered. This point could be demonstrated by extemporaneous preparations of suppositories containing Theobroma oil as their base. Theobroma oil, like many triglycerides, exhibits polymorphism. It exists in three different crystal forms each with different melting points. Suppositories are prepared by fusion of theobroma oil, when they are melted and brought to 60-70°C. The molten form is then poured into molds and quickly chilled in a refrigerator. If suppositories prepared by this method are removed from the refrigerator after a short time they will melt at 30°C, which makes their use impractical in the summer, and the patients will have difficulty in inserting them, since they will liquefy in the fingers. If the suppositories are prepared by heating the theobroma oil just a few degrees above its melting point, the suppositories will have a higher melting point and can be easily handled. This method of manufacture permits the crystallization nuclei of the more stable (higher melting point) β-forms to remain in the melt, which on chilling favors additional crystallization of the β-form. Fused theobroma oil heated to 60-70°C when chilled undergoes super cooling and α-form crystals develop, which have lower melting points. The α-form, being a metastable phase, slowly changes to β1 and to β-form.

Conclusions

Probably every organic medicinal can exist in different polymorphs and the choice of the proper polymorph will determine if a pharmaceutical preparation will be chemically or physically stable, or if a powder will tablet or not tablet well, or if the blood level obtained will be the therapeutic level to give the pharmacologic response desired. Thus, it is time that pharmaceutical companies, as a part of their pre-formulation studies, identify and study the stability of different polymorphs of each potential new drug, as they do the melting points or other physical characteristics.