Cocrystals
Cocrystals (or co-crystals), which are unique crystalline structures containing multiple components, have been known since 1844. The use of cocrystals containing pharmaceutical components was reported as early as 1895. Cocrystals have unique properties and have been shown to be stable and useful in pharmaceutical development. Advances have been made recently in methods of finding cocrystals and in generating them reproducibly using standard crystallization conditions.
Figure 1. Cocrystal Formation Schematic
Pharmaceutical companies are developing cocrystalline forms of new APIs, and some companies are searching for patentable cocrystals of generic or soon-to-be-off-patent APIs in order to establish intellectual property positions.
Property Improvement
Cocrystals have been developed in our lab to improve:
- Aqueous solubility
- Dissolution
- Hygroscopicity
- Bioavailability
- Stability
- Increase of Melting Point
- Purity of API
- Intellectual Property Positions
- Developability
Triclinic is uniquely qualified to carry out cocrystal screening and aid in the patenting and development of those found. Dr. Scott L. Childs, who leads our cocrystal development group, is a globally recognized expert in the cocrystal field and carries out cutting-edge research to improve understanding of the structure and properties of cocrystals and to develop new cocrystallization methods. Triclinic is the only CRO with a dedicated cocrystal team with the proven, published experience required to not only screen, but also accurately characterize cocrystals of your API. We use a phase diagram approach to screening.
Figure 2. Establishing phase relationships can lead to a more intelligent approach to solid-form screening and development as well as prediction of undiscovered solid-forms or instability. Important tools in establishing phase relationships are thermal analysis techniques such as diff erential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and increasingly, temperature-dependent XRPD. In-depth knowledge of the phase relations often leads to further re nement in synthetic procedures in an iterative fashion. New phases are characterized by their melting points and their stoichiometric domains. The latter is important for the many solids that are non-stoichiometric compounds. The cell parameters obtained from XRPD are particularly helpful to characterize the homogeneity ranges of the latter.
Screening and Selection
An important factor in the success of our screening process is the choice of reaction conditions. Reactions can be broadly classified as using stoichiometric or non-stoichiometric amounts of API and coformer. Stoichiometric reactions are performed as variations of a wet milling or solvent drop grinding process while non-stoichiometric reactions are a type of slurry conversion experiment. A wide variety of methods for facilitating nucleation and growth of a cocrystal are employed, including thermal, mechanical, and sonication processing. Solids are isolated and XRPD and/or Raman data from the solids are used to identify hits. Manual screening in individual vials is also performed for coformers that are not compatible with the parallel reactor technology.
Triclinic scientists are also highly proficient at binary melt (Kofler) screening. This thermal technique is an effective manual screening method as well as a valuable characterization tool.
Our standard cocrystal screen employs 47 pharmaceutically-acceptable coformers but up to 95 such coformers can be used in our extensive screen, An extensive collection of coformer data, including toxicological and polymorphism information, enables us to design API-specific projects as well as rapidly asses analytical data to determine which screening reactions are successful.
Figure 3. Use of Kofler technique for identification of cocrystals. Binary Melt of API and coformer demonstrates a third component (cocrystal) forming at the eutectic interface (Left Image). Triclinic utilizes multi-well reaction blocks developed at by Scott Childs to efficiently screen for cocrystals using minimal material.
Supersaturation Control and Formulation
An innovative aspect of Triclinic’s approach to cocrystal formulation is identification and control over supersaturation levels achieved during cocrystal dissolution. That can be achieved by directly manipulating the cocrystal solubility using pharmaceutically-acceptable excipients that are incorporated into a supersaturating drug delivery system. By using those excipients to tune a system for optimal performance, the highest practical supersaturated solution concentrations can be achieved while avoiding precipitation of the API.
The two phases of cocrystal formulation development are designed to 1) create and then 2) maintain API supersaturation. These two phases are often referred to in the literature as the “spring” and “parachute”.
1) Setting the Spring
Delivering APIs in ways that provide super-equilibrium concentrations constitutes the spring. A variety of formulation approaches have been used, including solubilized API, solid dispersions, nanoparticles, and inorganic carriers. The API can provide the spring itself if delivered in a high-energy form such as a non-crystalline solid or a cocrystal. Cocrystals offer the advantage over non-crystalline solids that the problem of physical instability to crystallization is avoided. To determine if a cocrystal provides a spring, well-designed, non-sink dissolution studies should be carried out. We have found that in general dissolution rates can be tuned based on the water solubility of the coformer, although the relationship of coformer water solubility to cocrystal water solubility is not always linear.
2) Opening the Parachute
The key to use of a supersaturating drug delivery system is to open the parachute, maintaining the concentration delivered by the spring long enough for absorption to occur. When using cocrystals, the spring concentration levels, the ratio of API and cocrystal solubility, the cocrystal dose, and the API crystallization rate must be considered. For example, the higher the supersaturation level delivered by the spring, the more driving force exists for API crystallization. Use of crystallization inhibitors in the formulation can delay API crystallization and increase the time over which supersaturation is maintained. (Figure 4). In another example, higher cocrystal loading in a formulation does not necessarily lead to higher exposure. Since lower loading provides a lower supersaturation level, API crystallization may be slowed (Figure 5).
Figure 4. Crystallization inhibitors are used to create a formulation that prolongs the supersaturated state. Inhibition of API crystallization in combination with a high supersaturation levelcan lead to higher plasma levels.
Figure 5. A formulation containing 1 mg of cocrystal AUC of 0.095 (0-30 min) whereas a formulation containing 2 mg of cocrystal had an AUC of only 0.051. The higher dose caused a correspondingly higher degree of supersaturation that led to more rapid crystallization rate of the API. The process of evaluating the dose effect in dissolution experiments is an important aspect of the formulation process.
Improved Development Results
Cocrystals have unique aspects that make them behave quite differently compared to polymorphs and salts, and this makes the solid form selection process atypical for cocrystals. We have seen viable cocrystals rejected from the development process because the routine characterization and analysis techniques used for evaluating dissolution rate were incorrectly applied to cocrystal systems. Triclinic has the hands-on experience with a wide variety of real-world cocrystal systems to help you avoid similar pitfalls. We have dedicated scientists that work exclusively on cocrystals, and working with Triclinic will bring this experience and focus to your team and improve the cocrystal development process at your company.
Purdue Pharma Example from McNamara et. al. Pharm. Res. 2006, 23, 18
Scott Childs of Triclinic worked extensively with Dr. Dan McNamara of Purdue Pharma to improve an API whose bioavailability was unacceptable. A cocrystal screen was performed using the methods previously described and one candidate was taken forward for further evaluation. A better dissolution profile (Fig 6) and subsequent bioavailability improvement in dogs (Fig 7) was seen. In that case a fortuitously slow API crystallization rate allowed higher plasma levels to be achieved by administration of neat cocrystal.
Figure 6. Intrinsic Dissolution (37 °C in water), The cocrystal dissolves 18× faster than API
Figure 7. Bioavailability study in dogs demonstrates ~4X AUC increase.
Let us help you improve your compounds
At Triclinic our focus on being the leader in the cocrystal field and our continuous innovation separates us from other CROs offering cocrystal screening services:
- The scientists at Triclinic have performed more the 200 cocrystal screens to date
- Our hit rate is higher (75% of the 32 APIs we screened in the last 12 months resulted in at least one cocrystal)
- We have the only staff, laboratory and screening process and equipment that has been dedicated exclusively to cocrystal screening for the past 10 years
- We have industry leading proven proprietary screening techniques that are only available at Triclinic
- Our database of pharmaceutically acceptable coformers is more diverse and better researched than any other
- Our cocrystal publications have had an industry-wide impact and have the highest collective number of citations. To view Scott L. Child's Bibliography, please click here.
- We collaborate with the leading academic cocrystal research groups
Nobody can match our experience and expertise in the field of cocrystals. If you want the industry leading cocrystal screen for your API, set up a consultation with Scott Childs at Triclinic to discuss your project.
For a discussion of cocrystals, as well as polymorph and cocrystal screening, see Dr. Stahly's article in Crystal Growth & Design 2007, 7, 1007-1026 here, and an article by Dr. Childs et al. in JACS 2004, 126(41), 13335-42 here.
