Polymorphism Identification and Control

What Is Polymorphism?

One Compound, Multiple Unit Cell Modifications

Crystalline materials can be characterized and distinguished according to the structure of their unit cell. The phenomenon of one chemical species showing more than one possible unit cell configuration is known as polymorphism. Many crystalline materials can form different polymorphs in order to minimize their crystal lattice energy under specific thermodynamic conditions. While the chemical nature remains same, the physical properties (solubility, dissolution, nucleation & growth kinetics, bioavailability, morphology and isolation properties) can vary between polymorphs.

What Process Challenges Does Polymorphism Cause?

Reduced Bioavailability and Patent Conflicts

Knowledge about stability of crystal forms and tightly controlled processing conditions are critical to obtain a desired polymorph. Often, a simple change in temperature, agitation, or solvent composition can cause the material to change from a metastable form (local energy minimum) to the stable form (global energy minimum). The change in crystal structure often means a change in the external shape, which can impact isolation properties.

If cube-like crystals change to thin platelets, filtration time can significantly be increased due to caking of the material on the filter. If the transformation forms a solvate, it often increases drying times until the additional solvent is evaporated. If formulators are used to a prismatic crystals and suddenly have to work with needles, formulation of the final product might not be possible. A more stable polymorphic form often shows lower solubility, which will reduce bioavailability and in vivo performance making a drug less effective.

Late discovery of a more stable polymorph canhave disastrous effects on the supply of a drug product and can even cause patent conflicts, if the more stable form is already patented.

How Is Morphological Transformation Identified?

Visualize the Impact of Process Parameters on Polymorph Transitions

In most crystallizations, it is necessary to obtain the same polymorph and morphology for every batch because the wrong polymorph would make the product unacceptable. However, in crystallization it is common for an unstable form and morph to appear first and later transform to a stable form. Offline endpoint analysis will document the final form but will miss the information whether polymorphism transformation occurred earlier in the process.

The use of in situ analytical tools is critical for developing knowledge of the crystallization behavior throughout the entire process. In situ particle size and count trends as well as in situ process images record the change of morphology with elapsed time. This allows critical investigation of the impact of processing parameters like temperature, agitation, and solvent composition on morphology and transformation kinetics at any time along the process.

Real Time Microscopy for Polymorphism

Visualize Polymorphs in Process

ParticleView Real Time Microscopy is an easy-to-use PAT tool that records high resolution images of particles and particle structures as they naturally exist in process. Each image is analyzed in real time providing a simple trend that follows particle size, count and shape under real process conditions.

Identify Physical Transformation

Monitor Changes on a Molecular Level to Understand Kinetics, Mechanism, and Pathways

Image processing although extremely powerful in the identification of various polymorphs  often requires a secondary technique to distinguish between polymorphs. Raman spectroscopy offers a powerful technique that allows for differentiation of desired polymorphs by looking at the differences at a molecular level. Raman utilizes the change in polarizability or electron cloud deformation of a molecular bond. Molecules exhibit "fingerprint" vibrational patterns and a Raman Spectrometer is able to identify different polymorphs by their characteristic fingerprints.

Polymorphs are chemical compounds that although have the same chemical formula, exhibit different lattice structure. Differences in the length and angle of the bonds will produce a different fingerprint allowing the Raman user to monitor polymorphism over time.

Reaction analysis utilizing these molecular fingerprints enables scientists to measure Crystallization processes and polymorph changes in real-time, providing information about:

• Reaction Kinetics
• Mechanism
• Pathways
• The influence of reaction variables on reaction products

In situ Raman spectroscopy allows the user to directly track reactants, reagents, intermediates, products and by-products as they change during the course of the reaction.  Raman provides critical information to scientists as they research, develop, and optimize chemical compounds and crystallization processes.

How Do You Analyze Polymorphism?

ReactRaman Raman Spectrometer

Introducing the compact, high-performance ReactRaman Raman Spectrometer, coupled with iC Raman 7 and trusted service and support, provides critical insight – even for the most challenging reactions.

One Click Analytics means that whether you are an expert, or new to Raman Spectrometers, data collection and analysis is fast and accurate.    

Polymorphism in Industry Publications

• Hao et al. – 2011 – The use of in-situ tools to monitor the enantiotropic transformation of P-aminobenzoic acid polymorphs
  
  
• Takeguchi et al. – 2016 – Effect of temperature and solvent of solvent-mediated polymorph transformation on ASP3026 polymorphs and scale-up
  
  
• Liu et al. - Investigation into the Cooling Crystallization and Transformations of Carbamazepine Using in Situ FBRM and PVM - Org. Process Res. Dev. 2013, 17, 1406-1412
  

Polymorphism Workstation

For Particle Monitoring and Control

Crystallization is a multistep unit operation, which depends upon effective process control in order to obtain final product of desired properties. A Polymorphism Workstation with in situ Process Analytical Technology (PAT) provides the necessary control over all essential parameters:

• Temperature, Stirring, pH, and Dosing with a Chemical Synthesis Reactor
• Particle Morphology and Complex Mechanisms with Real Time Microscopy
• Obtain Polymorph and Physical Transformations with ReactRaman Raman Spectrometer

A Polymorphism Workstation with in situ PAT provides real time process data for immediate interpretation, substantially reducing development time and cost for offline analytical work. 

Viewed from the outside a crystallization process may appear to be running smoothly. But hidden crystallization mechanisms are usually occurring that can dramatically impact the final outcome.

• Agglomeration can trap impurities
• Oiling out leads to poor control
• Secondary nucleation slows down filtration

This practical guide describes seven hidden mechanisms that can influence your crystallization process and outlines strategies to control them.