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CRYSFORMA
crystallization solutions
CRYSFORMA is a technology development unit, belonging to the Institute of Chemical Research of
Catalonia (ICIQ), oriented to offer complete scientific and technological support in the field of
pharmaceutical solid state development. We provide services for the discovery, analysis and
scale-up of polymorphs, salts and co-crystals of active pharmaceutical ingredients or intermediates.
Selecting the appropriate solid form of a pharmaceutical active compound assures optimum
physical and chemical solid state properties: solubility, dissolution rate, hygroscopicity and
stability. These properties can have a significant influence on the bioavailability of the final drug.
SERVICES OFFERED:
◗ Comprehensive polymorphism, salt and co-crystal screenings of a drug substance.
◗ Scale-up of the optimal polymorph, salt or co-crystal.
◗ Determination of the relative stability of different polymorphic forms.
◗ Development of reliable procedures to prepare selected polymorphs.
◗ Development of analytical methods for polymorph quantification.
◗ Crystallization of compounds difficult to crystallize or formerly only known as amorphous solids.
◗ Development and scale-up of robust crystallization procedures.
◗ Resolution of chiral compounds by selective diastereomeric salt crystallization.
◗ Crystallizations oriented to the preparation of single crystals and structure determination by
single crystal X-ray diffraction.
METHODOLOGY:
Av. Països Catalans 16
43007 Tarragona (Spain)
Phone: +34 977 920 205
Fax: +34 977 920 224
[email protected]
www.crysforma.com
CRYSFORMA has developed its own crystallization screening methodology based on the combination of several crystallization procedures. We use high-throughput crystallization systems
controlled by highly skilled scientists to maximize the information drawn from each experiment.
Our projects are always carried out in close collaboration with the client and adapted to the
customer’s needs.
POLYMORPHISM & CRYSTALLIZATION
CRYSFORMA offers complete scientific support to discover and characterize the most relevant polymorphs of a drug and to select the candidate with optimal solid state properties.
Polymorphism, the ability of a chemical compound to crystallize in more than one crystalline
phase, is a key issue in the pharmaceutical industry. Different polymorphs can have different
physical and chemical properties, and thus can have an influence on the bioavailability of the
pharmaceutical compound. Additionally, polymorphism is key to patent strategy, as different
polymorphs can give rise to independent IP claims.
Moreover, the relative stabilities of the different polymorphs must be known in order to avoid
unwanted polymorph transformations during production of the active pharmaceutical ingredient or in the final pharmaceutical compound.
TYPE OF STUDIES
◗ Initial or fast polymorphism screening for early stage candidates.
◗ Comprehensive polymorphism study of a drug substance.
◗ Determination of the relative stability of the different polymorphic forms.
◗ Scale-up of the selected polymorphs.
◗ Development of analytical methods for polymorph quantification.
◗ Crystallization of compounds that are difficult to crystallize or that are formerly
known only as amorphous solids.
◗ Crystallizations oriented to the generation of single crystals for single crystal
X-ray diffraction structure determination.
Av. Països Catalans 16
43007 Tarragona (Spain)
Phone: +34 977 920 200
Fax: +34 977 920 224
[email protected]
www.crysforma.com
METHODOLOGY
The unit has developed its own crystallization screening methodology based in the use of several
crystallization procedures, oriented to obtain the thermodynamically stable phase as well as
kinetically favoured phases. Moreover, solvent-mediated as well as solvent-free crystallization
procedures are assayed. We use small scale high throughput crystallization systems controlled
by highly skilled scientists to maximize the information drawn from each experiment.
SALTS & CO-CRYSTALS
CRYSFORMA offers systematic salt & co-crystal screening studies to
discover and select the salt derivative or co-crystal of an API with optimal solid state properties.
◗ Salts: Preparation of a salt is the classical strategy to optimize the solid state properties of an
active pharmaceutical ingredient. Salt derivatives can improve crystallinity, solubility and stability of a pharmaceutical compound, and are often chosen instead of the free acid or base.
◗ Pharmaceutical co-crystals: In recent years, the development of a pharmaceutical
co-crystal has become a novel strategy to improve the solid state properties of an API.
Co-crystals are an alternative to salts when these do not have the appropriate solid state properties or cannot be formed due to the absence of ionizable sites in the API.
TYPE OF STUDIES
◗ Salt and co-crystal screening of pharmaceutical ingredients with selected
counterions or co-crystal formers.
◗ Characterization of crystalline salts and pharmaceutical co-crystals.
◗ Development of reliable preparation procedures.
◗ Scale-up of the selected salt or pharmaceutical co-crystal.
◗ Polymorphism study of the selected salt or co-crystal.
◗ Resolution of chiral compounds through selective diastereomeric salt crystallization.
METHODOLOGY
Av. Països Catalans 16
43007 Tarragona (Spain)
Phone: +34 977 920 200
Fax: +34 977 920 224
[email protected]
www.crysforma.com
The unit has developed its own salt and co-crystal screening methodology based in the use of
selected crystallization procedures in an optimized group of crystallization solvents. The
methodology allows performing 1000 crystallization experiments from 10 g of starting API
under controlled conditions. We use small scale high throughput crystallization systems controlled by highly skilled scientists to maximise the information drawn from each experiment.
PXRD ANALYSIS
SOLUBILITY
Polymorph quantification and
detection limit determination
Solubility screening
Development of analytical methods for the
quantification of a given polymorph in a mixture and the determination of the limit of
detection (LOD). Crysforma has developed a
measurement procedure to be able to quantify a given polymorph and determine its presence with very low detection limits (typically
in the range of 0.3 and 1%, depending on the
API). The same procedure can be applied in
mixtures of different crystalline products (API
1 + API 2, API + excipient, etc).
Fast analysis service
Crysforma offers a fast and reliable powder
X-Ray diffraction service, including several
analysis types:
◗ Crystalline phase identification, comparing
against standards defined by the company.
◗ Measurements according to specific analytical methods developed by Crysforma.
◗ Component search in specialized databases.
Variable temperature PXRD
On its own or in combination with other
thermal analysis techniques, VT-PXRD can
provide useful information regarding crystal
structure, dehydration / desolvation, phase
transitions, melting and decomposition of
pharmaceutical compounds.
Solubility screening studies provide information
on the best solvent media for a given crystallization process. Solubility data is also relevant
during pre-formulation evaluations of APIs.
Solubility curves and metastable zone width in
a given solvent are determined with small
amount of API and in a short period of time.
Intrinsic dissolution
An additional characterization of bulk drug
substances and excipients is the measurement of
intrinsic dissolution rates. Its determination can
be in some cases important since bioavailability
of an API is influenced by the dissolution rate. Furthermore, intrinsic dissolution tests are a way to
prove chemical purity, batch-to-batch consistency
and sameness after changes in production.
OTHER SERVICES
Amorphous content
Mechanical stresses during processing may introduce small amounts of amorphous material which
can have a relevant effect on the products properties, including solubility and stability. Crysforma
applies several available analytical techniques
(PXRD, thermal analysis, GVS) to determine small
amounts of amorphous phase in a crystalline solid.
Solid form hygroscopicity and stability
Use of gravimetric vapour sorption (GVS) and
climatic chambers to determine the effects of
relative humidity and temperature on the solid
form of interest.