For over a quarter century, SSCI has been assisting the world’s pharmaceutical and biotechnology companies in drug substance and product development and analysis, intellectual property management, and diverse solid-state chemistry control issues. In working with over one thousand active pharmaceutical ingredients and hundreds of drug products, we’ve developed a comprehensive understanding of how to maximize development success. Whether you need an in house short course on chemical development, problem solving, or technical/scientific advice on intellectual property, our group of experts can help.
SSCI can help solve your most difficult solid-state problems. For example, when the solid form of a pharmaceutical company’s clinical trial material inadvertently varies from batch to batch, we can determine the properties of the different forms used, perform dissolution testing, recommend whether a bridging study needs to be carried out, and propose specific bridging study content. When a new polymorph appears during clinicals or after commercialization, we can analyze the solid form issues and assist in rapid reformulation or recommend effective process changes.
SSCI scientists are experts at contaminant analysis for both API and drug product and we have experience with a wide variety of dosage forms. We investigate causes of failure to meet specifications, particularly dissolution specifications.
We can help when a new solid form appears or when drug product fails to meet specifications.
SSCI is also experienced in the investigation of drug product stability and integrity failures such as friability and chipping of tablet coating or formation of haze in parenteral products. We determine the effect of excipients on product stability and we have strategies for solubilization of poorly soluble drugs.
In the specialty and industrial chemicals industries, we help clients improve the solubility or flow properties of their solid products.
Our clients come to SSCI for the most trusted and comprehensive cGMP solid state chemistry services available. Below are some common problems we solve and approaches we take using our systems and computational services. Our new software allows us to determine much more with powder pattern data than ever before and do so more quickly. This translates into more informed and faster decision making capabilities for our clients.
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Identifying functionality at crystal faces to aid in morphology design
Improving API stability by monitoring and reducing levels of crystal imperfections
Understanding unexpected XRPD patterns during manufacturing or process development
Controlling flow properties during milling by monitoring microstructure
Improving stability of amorphous material
Finding a new form by studying X-ray amorphous materials
Carrying out cGMP quantitative mixture analysis
Using order-disorder relationships as a new method of patenting solid forms
Distinguishing Solid Forms
A common problem in polymorph screening is uncertainty in assignment of unique XRPD patterns. Even for the experienced scientist, it can be difficult to know whether a pattern represents a new solid form, a mixture of components, or simply a variation in extent of hydration or solvation. TRIADS indexing software is used routinely at SSCI to rapidly provide the structural information necessary to assign forms without having to attempt growth and diffraction of single crystals. For example, in a project at SSCI, two distinctive crystalline powder patterns were observed during solid form screening. The first pattern was matched to a known unsolvated form of the API. The second pattern had many peaks in common with the first, but the relative peak intensities were slightly different and additional weak peaks were observed. By visual inspection it could not be determined whether this second powder pattern corresponded to a mixture or to a new crystalline polymorph/solvate. Indexing immediately determined that the new form was indeed a single phase crystalline form with a slightly smaller unit cell volume than the known form. As the general multiplicities of the space groups were equivalent, the slightly smaller volume indicates that the new crystalline form is an unsolvated polymorph of the original form. [top]
Identifying Functionality at Crystal Faces to Aid in Morphology Design
Software can be used to determine the chemical functionality at crystal faces. This information provides the basis for experimental approaches to modify the crystal shape. For example, SSCI assisted in a project where the drug substance could only be produced as fine needles. The morphology caused severe handling problems and made it impossible to obtain a single crystal structure. Computational methods were used to obtain the unit cell parameters and molecular packing from powder data. This analysis gave the functional groups present on the fast-growing faces of the needles and enabled investigation of the use of additives during crystallization to slow the growth at those faces. [top]
Improving API Stability by Monitoring and Reducing Levels of Crystal Imperfections
Different crystallization methods can produce significant variation in the properties of a drug substance even when the solid form is the same in each case. For example, voids, fractures, and other physical imperfections can influence the material’s moisture and solvent uptake, ultimately influencing stability. SSCI’s proprietary software is especially suited to analysis of microstructure and has been used to analyze batches from different crystallization processes in a study to select conditions that produce the most stable, consistent drug substance. In one case, attempts to directly crystallize the most stable form always produced a disordered crystalline material with relatively short crystalline correlation lengths and inadequate stability. However, by stressing a solvated crystalline form under high humidity conditions it was possible to form crystalline material of the most stable polymorph with increased crystalline perfection with significantly increased crystalline correlation lengths. The increase in crystalline perfection corresponded with an increase in material stability. The crystalline correlation lengths were monitored during the study. [top]
Understanding Unexpected XRPD Patterns During Manufacturing or Process Development
During drug development there can be situations where drug substance or drug product fails to meet specifications. In one project at SSCI, a client’s drug substance showed extra peaks in its XRPD pattern. It was necessary to rapidly find out if the extra peaks were due to a contaminant, a change in solid form, or a change in morphology. Proprietary software was used to match these new peaks against all known crystalline forms of the drug molecule and possible crystalline contaminants from the production process. No single crystalline solid form was found that would match all the new peaks. Indexing of the original crystalline X-ray powder pattern showed that all of the new peaks could be described by the original crystal unit cell but that no simple change in morphology or preferred orientation could account for all the peaks. Subsequent analysis of the molecular packing using Rietveld techniques indicated that a randomizing of a single functional group could describe all the observed new peaks. The randomizing most likely occurred during the crystallization of the drug substance rather than at any other point of the production process and was most likely associated with a reduction in temperature or anneal time. [top]
Controlling Flow Properties During Milling by Monitoring Microstructure
Mechanical processing of any crystalline drug substance will introduce a certain amount of disorder into the crystal lattice. This disorder can be described by a change in microstructure using the primary variables of crystal size and lattice strain. Changes in microstructure are often directly related to changes in physical properties such as solubility. One example involved a crystalline drug substance that was relatively sensitive to milling. Using full XRPD pattern fitting methods the crystalline microstructure was characterized as a function of milling variables and correlated with mechanical flow properties to determine reasonable mechanical limits for the milling process. [top]
Improving Stability of Amorphous Material
For drug molecules that are difficult to crystallize or have poor dissolution profiles, the amorphous state may be the only development option. However, to develop a successful amorphous formulation, the complex issue of long-term stability must be addressed. Organic solid forms that give X-ray amorphous diffraction patterns may have very different microstructures and local molecular structures, which can be related to differences in long term stability. Furthermore, many methods of producing amorphous material generate isolated regions of crystalline material (polymorphic memory), which will act as nucleation centers further reducing the overall stability of the amorphous material. Within SSCI, software has been used to select the most appropriate methods for producing amorphous material to give the lowest energy local packing and least amount of polymorphic memory. Through refinement of the most appropriate production methods, significant improvement in the long term stability of amorphous has been achieved. [top]
Finding a New Form by Studying X-ray Amorphous Materials
A number of commercially successful crystalline drug products have been discovered/ manufactured via the amorphous state. At SSCI, X-ray amorphous patterns generated during a solid form screen are analyzed to determine their propensity to crystallize towards known or unknown crystalline forms. One particular molecular solid form screen performed at SSCI gave two distinct crystalline polymorphs and numerous examples of amorphous material. The X-ray amorphous patterns could be broadly differentiated into 3 groups. Characterization of the local molecular order associated the most frequently-observed X-ray amorphous pattern showed that it was a true amorphous material. The majority of the remaining X-ray amorphous patterns were then determined to be disordered variants of the most stable crystalline polymorph. The few remaining unassigned X-ray amorphous patterns were not related to any of the crystalline polymorphs nor were they due to a true amorphous form. Subsequent stressing of the material that generated the unassigned X-ray amorphous patterns gave rise to a new crystalline polymorph. [top]
Carrying out cGMP Quantitative Mixture Analysis
At SSCI, a number of cGMP validated quantitative analysis methods have been developed that make use of X-ray diffraction data. With quantitative limits typically between 0.2% and 5.0%, these provide a robust and sensitive means for controlling and monitoring production processes. X-ray methods are especially useful where polymorphic interconversion or amorphous/crystalline interconversion is expected. A number of different methods have been employed for quantitative analysis including PLS, full pattern statistical analysis and Rietveld. In one particular quantitative method used for lot release certification, the active drug component could appear with two different morphologies and slightly different crystalline unit cells. This significant variation in the X-ray pattern of the primary analyte made Rietveld an ideal choice for the quantitative method. Within the Rietveld model, the morphology and crystal unit cell were allowed to vary within limits during the quantitative analysis. [top]
Using Order-disorder Relationships as a New Method of Patenting Solid Forms
With the increasing use of larger organic molecules for drug products, the appearance of disordered-crystalline forms is becoming more common. A single crystalline polymorph of a large, flexible organic molecule can exist with a wide range of possible crystalline microstructures. As the crystalline polymorph becomes more disordered and the once sharp, well defined X-ray peaks begin to broaden and merge into diffuse halos. This type of disorder gives a continuum of possible XRPD patterns – representing a significant challenge for the patenting of the solid form. For one such drug molecule, it was possible to uniquely describe the complete family of expected disordered forms – even those not yet observed. This gives the potential for increased robustness and self consistency for the solid form patent. [top]