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product name ▶ Polymorph screening
release time 2015-09-19
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▶ Polymorph screening
Date: 2015-09-19 Course Instructor Course Instructor
Guided by the initial crystallization knowledge, we design the relevant experimental space including solvent, temperature, humidity (water activity) etc, systematically employing the highest possible diversity of the screening methods and dimensions to ensure a maximum probability in finding all solid forms. Specific areas including: ◆ Screen all possible solid forms of a new chemical entity ◆ Select the optimum solid form early in drug development ◆ Develop a crystallization process that assures control of solid form ◆ Produce a drug product with stable solid form through expiration Besides commonly utilized crystallization methods, other screening approaches might also be applied, for instance:   (1) Dry and solvent-drop grinding (2) Spray drying and freeze drying (3) Lyophilization (4) Crystallization from the melt (5) Compression (6) Sonication (7) Supercritical antisolvent (SAS) Further reading: Allesø M, Tian F, Cornett C, Rantanen J, Journal of Pharmaceutical Sciences ...
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Guided by the initial crystallization knowledge, we design the relevant experimental space including solvent, temperature, humidity (water activity) etc, systematically employing the highest possible diversity of the screening methods and dimensions to ensure a maximum probability in finding all solid forms. Specific areas including:

◆ Screen all possible solid forms of a new chemical entity

◆ Select the optimum solid form early in drug development

◆ Develop a crystallization process that assures control of solid form

◆ Produce a drug product with stable solid form through expiration


Besides commonly utilized crystallization methods, other screening approaches might also be applied, for instance:  

(1) Dry and solvent-drop grinding

(2) Spray drying and freeze drying

(3) Lyophilization

(4) Crystallization from the melt

(5) Compression

(6) Sonication

(7) Supercritical antisolvent (SAS)

Further reading: Allesø M, Tian F, Cornett C, Rantanen J, Journal of Pharmaceutical Sciences 2010, 99, 3711-8


Hydrate/solvate

Hydrate is not a rarely encountered solid phase. In fact, it has been estimated that at least every third drug compound can form a hydrate {Morris, 1999 #800}.

Hydrate formation - or dehydration of a given hydrate - may affect dramatically the performance of the final medicinal product. Bioavailability of given compound is affected through difference in solubility and dissolution rate between anhydrate and hydrate. Hydrate can also be part of the overall IP protection strategy for a given compound, which is crucial to the pharmaceutical industry. Therefore, it is important to screen possible hydrate form(s) in the early phases of the drug development process.



The presence of DH was considered to be the main cause for therapeutic failures of marketed CBZ tablets (Tegretol®) and resulted in a recall of CBZ tablets in 1988, leading to a dramatic market loss.

Hydrate stability is closely related to its classification, which requires a deep understanding of the classification.


Isolated site hydrates

Definition: water molecules are isolated, in another word, not in contact with one another.

Characteristics: Removal of water from isolated site hydrates typically requires a certain higher energy than those channel hydrates. But once the dehydration starts, the majority of water will be escaped promptly.


Analytics: when analyzed by thermal methods, the dehydration of isolated site hydrates exhibits sharp dehydration endotherms (indicated by sharp endothermic peaks in differential scanning calorimetry (DSC)), and narrow weight loss ranges (observed with thermogravimetric analysis (TGA)). Also, in infrared spectroscopy, these crystalline water molecules show sharp OH bands.

 

Channel hydrates

Definition: the crystalline water form channel-like chains along a given crystal axis.

 

Characteristics: The water molecules in this class form hydrogen bonds with the adjacent water molecules. The existence of water channel facilitates the water elimination from the hydrate crystals. Once the surface crystalline water is removed, the inside water will start escaping one by one through the water channel, which results in a relatively low thermal stability of the channel hydrates.


Analytics: These hydrates usually have lower onset dehydration temperature than the isolated site hydrates. Also, the dehydration peaks in DSC is rather broad, and TGA weight loss range is rather wide too. Although they also have sharp OH bands in infrared spectra, these bands are orientated at a relatively low frequency indicating a lower bonding energy.

 

Ion-associated hydrates

Definition: contain ion-coordinated water.

 

Characteristics and analytics: high dehydration temperatures are characteristic for this class because of the strong bond strength of this class.


Polymorphic hydrate

Polymorphic hydrate can be defined as two or more hydrates having the same chemical composition and same molar ratio of water in the crystalline lattice, differing only in their crystal packing arrangements (as illustrated below).

Properties such as mechanical properties, physical and chemical stability are often different between a hydrate and its corresponding anhydrate, which makes screening and stabilization of the selected form crucial. The same applies to the hydrate polymorphs. Different polymorphs of hydrate are also found to exhibit different properties.




Although they are both NF monohydrate, their physico-chemical properties vary, for instance aqueous solubility in water at 23 oC is 131 ± 12 μg/ml and 110 ± 4 μg/ml for monohydrate I and II respectively.


Further reading: Tian F and Rantanen J, Food Biophysics 2011, Mar 6, 250–258

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    release date: 2015 - 09 - 19
    Guided by the initial crystallization knowledge, we design the relevant experimental space including solvent, temperature, humidity (water activity) etc, systematically employing the highest possible diversity of the screening methods and dimensions to ensure a maximum probability in finding all solid forms. Specific areas including: ◆ Screen all possible solid forms of a new chemical entity ◆ Select the optimum solid form early in drug development ◆ Develop a crystallization process that assures control of solid form ◆ Produce a drug product with stable solid form through expiration Besides c...
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