Polymorph in Drugs

Molecules exist in nature in any of the three states viz., solid. liquid and vapour. But most of the molecules, organic and inorganic , exist in solid states. It is very interesting that if these solid state molecules  have therapeutic benefits, they’re used as a drug substance.  

In a solid state, the  molecules or the elements   exist as crystals  which are  oriented in a organised or disorganised ways. Hence multiple orientations are possible for a molecule. In a pharmaceutical drug, these different crystalline orientations are named as Polymorphs. 

Polymorphism may be defined as the ability of a compound to crystallize in two or more crystalline phases with different arrangements and/or conformations of the molecules in the crystal lattice. Hence, polymorphs are different crystalline forms of the same pure chemical compound. 

Since these crystalline forms are oriented differently, their free energies are also different which makes them as unique by having differences in their physical properties like melting point, solubility etc.  These differences in the properties make  pharmaceuticals scientists to discover more useful drugs by having therapeutic benefits to patients.

Other than the crystalline forms, molecules can also exist as amorphous, solvates, hydrates forms. In amorphous form, the elements are in a disorganised way. In pharmaceuticals, due to nature of existanace of solvates and hydrates, scientists have discovered many drugs in the form of salts which have therapeutic benefits.The solvates are also termed as meta stable forms. Sometimes these metastable polymorphs are significant due to their higher solubility property combined with lower hygroscopic in nature.

The stability of the molecule plays an important role in developing pharmaceutical product.

Thermodynamically more stable polymorph is preferred during drug formulation due to associated lower  free energy. Hence these stable forms will be protected by the manufacturers by taking patents. In such cases, polymorphs of different salts, solvates will be developed which are stable with appropriate packing, excipients  to overcome the patents. In any case, monitoring and controlling the presence of other polymorphs in the drug is important as it may affect the solubility as well as to avoid IP issues. Hence manufacturers ensures that pure polymorphs is retained in their manufactured drugs till its expiry in the market through polymorphic screening during drug development, manufacturing, storage stability.

Various methods are available to crystallize different polymorphs of a compound such as cooling, sublimation, recrystallization from single or mixed solvents, altering the pH of the solution etc. In the pharmaceutical industry, different polymorphs are usually prepared by recrystallization from solutions, employing various solvents and different experimental conditions and  rate of agitation.

Inadvertently environments like relative humidity, temperature, pressure, presence of residual solvents, operations  like milling, micronisation, usage of inadequate packing materials etc can influence / trigger the conversion of one form to another. 

Hence a well designed straregy of appropriate process controls, usage of right packaging materials are required to obtain stable polymorphic drug from production, packing and marketing.

Different polymorphs will also have different mechanical properties  such as hardness, powder flowability, compressibility and bonding strength which can adversely affect the solubility by producing lower dissolution of the drug than required dissolution rate. 

Inorder to measure the level of one polymorph in another and to check the purity of desired polymorph, there are multiple analytical techniques available to identify and quantify at lowest levels. The presence of other polymorphic data sometimes will be generated by competitors for possible IP infringement litigations as a breach of their innovation. 

The various analytical technique used are

1. Powder XRD

2. Solid state NMR

3. Raman spectroscopy 

4.  DSC

5.  IR 

6.  SEM

7.  DVS etc.

Solid state NMR

Small changes in conformation  or  electronic structure cause  noticeable differences in chemical shift in NMR. Different crystal forms can have relatively large changes in the chemical shifts.

Solid state stability studies are regularly carried out at elevated temperatures and humidities to study polymorphic interconversions, hydrate formation, recrystallization of amorphous compounds. 

By solid state NMR, it is possible to quantity mixtures of crystalline forms as well as mixtures of crystalline and amorphous forms without the need of a standard curve  which makes the technique a wonderful tool in pharmaceutical drug formulations.

It is a nondestructive and noninvasive technique and can simultaneously look at both the API and excipients without the need of physical separations. 

DSC 

Differential Scanning Calorimeter (DSC) is the study of molecules thermal behaviour in terms of heating or cooling. DSC raw data shows heat flow (power in mW) plotted against temperature  obtained by the heat  difference between the sample and reference.

DSC is used to differentiate between polymorphs on the basis of melting point  as well as transformation behavior of metastable systems and hence to evaluate the polymorphic forms. 

DSC is an invasive technique which involves melting followed by transformation happens hence limited information can be obtained.

To overcome the shortcomings of DSC, an evolved Modulated Temperature  DSC (MTDSC) is used by scientists in the recent past with more application are developed.MTDSC generates  data with small  observed perturbation which are superimposed on the conventional linear signal. 

MTDSC allows to measure the heat capacity of the sample by a function of temperature. It involves by measuring overall signal (the total heat flow) and subtracting the heat capacity signal (the reversing heat flow) , it is possible to obtain the kinetic component associated with non-reversing responses such as crystallization (the non-reversing heat flow). 

The instrument therefore gives 3 signals in a single heating run, alllowing the heat capacity, kinetic and total heat flow components to be delineated. MTDSC has been used to study of amorphous systems  than of crystalline forms.

Though DSC have some limitations, by interfacing with other techniques like PXRD, NMR it allows us to understand the thermodynamics and kinetics of different polymorphs.

PXRD

Powder X-ray Diffraction (PXRD) is a powerful tool in identifying different crystalline phases. High-resolution PXRD provide information about the phase composition of crystalline samples, PXRD  is the most reliable technique to identify polymorphs. When a crystalline powder is exposed to an x-ray beam, it produces a diffraction pattern that is unique to that crystalline form. We can compare  that pattern with other polymorphwith a high degree of certainty.

The differences between the various crystalline forms can be identified by examining the peak positions (2theta) and intensities.

Small changes in the X-ray powder patterns due to the appearance of new peak, disappearance of some peaks can indicate the presence of a new polymorph.

In pharmaceutical industry, the regulatory agencies are insisting to identify the drug polymorph and its stability during storage as well as to control the other undesired polymorphs as their presence may adversary affect the bioavailability.

There are two types of polymorphic screenings, identification test with known polymorphic pattern. The second one is limiting the undesired polymorphic form in the drug by using quantitative methods. Quantification of other forms in drugs is important to avoid IP issues as well as to ensure bioavailability. In such methods, the need of establishing limit of detection (LOD) to the practically lowest level is critical and hence instrumentation sensivity plays a major role.