Characterization techniques in ascertaining the purity of polymorphs.

Hi everyone.I hope you are steeming on. For some time now,I have been writing on preparation of polymorphs in pharmaceutical industry. From the previous posts, I discussed about the thermodynamics of crystallization, the various phase transformation that takes place before you can have a solid.

Actually, the thermodynamics of crystallization is a bit complex like I earlier discussed, but because of it wide application in science and not only in the pharmaceutical industries, it should be understood. Knowledge of the various phase transformation that a substance undergo before it becomes solid is essential.

In this post today, I will be writing on the techniques used in analysing the purity of our pharmaceutical product. Sit down and enjoy the ride.

In the modern day drug analysis, several analytical activities are required in which the goals of the analysis is to detect, elucidate the structure and quantitatively determine both the organic and inorganic component, and to determine the left over of used solvent in the pharmaceutical formulation.

Analytical activities are routinely carried out in the industry to determine the quality and stability of the drug produced. This is always done to ascertain the purity of the drug.

Level of various Active Pharmaceutical Ingredient (API) in drug formulation have been studied by various analytical method. Some of those analytical methods will be discussed in this post.

In following every standard procedure, every stage from raw material analysis to intermediate and final product analysis is required in the industry.

Based on this needful standard procedure to be followed, I will do a brief description of characterization techniques of polymorphs here.

Some of analytical technique employed by scientist to explore into the purity of polymorphs are thermal analysis, thermogravimetric analysis, differential scanning calorimetry, Infrared spectroscopy, powder X-ray diffraction (XRD), optical and electron microscopy,, incoherent inelastic neutron scattering (IINS)

Extensive look at some of the listed method gives a deep knowledge of polymorphs characterization. Starting with thermal properties, it is usually obtained by running differential scanning calorimetry and thermogravimetric analysis.

The thermal analysis of polymorphs involved the study of how the polymorphs transform with temperature.Method used depends on the property of polymorphs to be study or measured which may include, differential scanning calorimetry(DSC), thermogravimetric analysis.(TGA), differential thermal analysis, dielectric thermal analysis, evolve gas analysis(EGA) and many more.

Any of the thermal analysis can be matched with Fourier Transform Infrared spectroscopy (FT-IR),for example, thermogravimetric analysis (TGA) couple with FTIR can be used to characterize and differentiate between various polymorphs.The function of the Fourier Transform Infrared spectroscopy (FT-IR) in thermal analysis is to assist in the identification of polymorphs by showing variation in frequency, band shapes, relative intensity, and number of bands produced by polymorph under study.

An FT-IR INTERFEROGRAM By Sbyrnes321 - Own work, CC0,
Spectra differences of polymorphs gives conclusion to the internal structure arrangement of crystals.When FT-IR spectroscopy is not use in the identification of polymorphs, Raman spectroscopy is a good alternative and a perfect nondestructive method for the study of polymorphs.

Raman spectroscopy, provides a better Spectra selection in understansting polymorph crystals.

Only recently did Raman spectroscopy gained popularity in the world of routine application in analytical chemistry. The method depends on light scattering, whereby incident radiation got scattered by molecules of compound under examination. The light scattered light consist of photons with equal frequency similar with that of incident radiation, the scattered light also contain some amount of photon with shifted frequency (changed frequency).

Raman Spectroscopy energy level:By Moxfyre, based on work of User:Pavlina2.0 - vectorization of File:Raman energy levels.jpg, CC BY-SA 3.0,
Raman spectroscopy is a multifaceted means in analysing a wide range of samples.The method fix most of the shortcomings of other spectroscopic methods.It's employed for qualitative and quantitative analysis of polymorphs.When it is used for qualitative screening, it measure the frequency of radiation scattered, and when it is used for quantitative screening, it measured the magnitude of how the radiation is scattered.

This analytical technique (RS) can gather spectra information from the sample exterior several millimeters into the sample volume. A case study of polymorphs of Ranitidine hydrochloride which is a group of drugs referred to as histamine-2 blockers, which reduce the level of acid been produced by the stomach.The drug prevent and is also used for treatment of stomach ulcer.

Ranitidine: By Ayacop - Own work (created with bkchem+inkscape, before Vaccinationist redraw with Adobe-Illustrator), Public Domain,

A series of spectra of the polymorphs collected starting from the exterior coating and proceeding into the bulk of the Ranitidine hydrochloride tablet. Each of the collected spectrum got contribution from the sample coating and the material bulk,how ever, the relative contribution of each of the component to the spectrum are not the same with the ones obtained with depth.
The pure Spectra of the coating and the volume of the polymorphs is obtained by subtracting between spectrum obtained.

Apart from the Vibrational Spectroscopic Method employed in polymorph characterization, another characterization technique is X-RAY powder Diffraction (XRD). It's a non-spectroscopic method which is used to determine polymorphic form of a compound using the variation related with the unit cell size or area.

X-ray crystallography characterizes crystalline pharmaceutical product. This is done by securing a structural solution by single-crystal X-ray crystallography.The crystallographic information gotten can also be utelized to obtain a powder Diffraction pattern for a specific crystalline form which can then be a reference arrangement for X-ray powder Diffraction(XRPD) analysis.

The X-ray powder Diffraction method is on the basis of the interaction of a monochromatic x-ray beam and a crystal. The various planes of molecules or atoms present in a crystal act as a grid (grating) for the x-rays. Bragg equation gives the conditions under which positive interference of the dispersed x-ray beam is to takes place.The equation follow that for monochromatic x-ray, the angle of diffraction completely rely upon the spacing of the crystalline component.

The pattern given by X-ray Diffraction,that is the intensity against the scattering angle is distinctive for all polymorph of a compound. Its this property that makes polymorphic identification easy by X-ray Diffraction.

Another characterization technique in polymorph identification is the use of Scanning Electron Microscopy (SEM).The technique generally produces image of the substance under examination by scanning the sample exterior when a beam of electron is focused on the sample surface.The beam of electrons focused on the surface interact with samples atom, giving different signals that is rich with information obtained from sample surface arrangement and composition.

Schematic diagram of SEM,By Schema_MEB_(it).svg: User:Steff, modified by User:ARTEderivative work: MarcoTolo (talk) - Schema_MEB_(it).svg, CC BY-SA 3.0,

The electron bean from SEM is examined in a raster scan pattern, then the position of the beam is joined with the signal detected to produce the crystal image,and with that, the polymorph is identified.

SUMMARY

In summary, I discussed about various techniques employed in pharmaceutical industry in identification of polymorphs since it is imperative that the true structure of the polymorph in the drug should be ascertained.The structure should be fully understood since the pharmaceutical industry get patent for a specific polymorph ,it will be detrimental to their brand name if it was eventually discovered that they produce another polymorph.

The techniques explained above are mostly combined by pharmaceutical industry before they could give their product a specific name.

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