Renovo Research provides cocrystal screening and salt screening services

What is a cocrystal?

Cocrystals provide valuable new crystalline solid form options, especially for molecules that cannot form salts.

A cocrystal is a crystalline molecular complex that is made up of two or more components, where a component is an atom, ionic compound, or molecule. The molecular components consist of stoichiometric amounts of the API plus another molecule, forming a hydrogen bonded complex. The second molecule in the cocrystal, the “coformer”, will be a pharmaceutically acceptable non-toxic molecule. Cocrystals are stable, patentable solid forms that provide a unique way of altering physical properties of active pharmaceutical ingredients.

Cocrystals, like salts, can alter the physical properties of an API solid form. Cocrystals can:

Increase solubility and dissolution rate of poorly soluble APIs
Improve chemical stability in the solid state
Avoid API forms prone to hydration or polymorphism issues
Crystallize APIs previously isolated only in amorphous or poorly crystalline form
Purify compounds or separate enantiomers
Improve development problems related to the crystalline form of the API
Increase the melting point of low melting APIs
Decrease solubility for extended release formulations

Cocrystals of Pharmaceuticals

Cocrystal Technology

The selection of the solid form of an API has a significant effect on product performance. Polymorphs, hydrates, and salts are the commonly available options if a crystalline form is desired. Cocrystals present an additional option, and a very significant one if the API is non-ionizable or unable to form effective salts.

If the unique cocrystal properties can be leveraged to create the basis of a drug formulation that cannot be duplicated without the use of the cocrystal, the cocrystal patent will preserve market exclusivity beyond the expiration of the molecule patent or any FDA exclusivity.

Renovo's cocrystal screening technology is used to identify and establish new IP for new cocrystals of an API. The improved cocrystal properties are used to develop a drug delivery mechanism that will create the product improvement.

Cocrystals can create improved physical properties

The primary focus in most cocrystal projects is improving the solubility of a poorly soluble API. Especially for non-ionizable APIs or APIs that do not form salts, cocrystals represent a significant opportunity to identify crystalline forms with dramatically improved solubility and dissolution rate.

In addition to improving solubility, cocrystals can be used to reduce hygroscopicity, generate crystalline forms of non-crystalline materials, purify or resolve an API, or stabilize unstable molecules.

In situations that require amorphous, lyophylized, spray-dried, micro or nano-sized particles or similar extreme processing conditions, cocrystals may provide the required properties in a crystalline form that can perform as well or better without any additional processing.

Phase Diagram Directed Cocrystal Screening

Cocrystal Screening at Renovo

Cocrystals are identified using a screening process in which the API is paired with each potential coformer molecule in order to determine if that API:coformer pair can form a cocrystal. The success of each screening experiment is highly dependent on the methods and crystallization conditions employed.

The cocrystal will be the thermodynamically preferred product in a system that contains saturated coformer and saturated API. Under those conditions cocrystals, if they exist, will form. The reaction composition is directed towards an appropriate area of the phase diagram by selecting solvents, or more commonly solvent mixtures, in which both the API and coformer have similar solubility and are saturated.

Using Phase Diagrams

The red area of the phase diagrams above is where the cocrystal is the least soluble solid form at equilibrium. The Renovo screen is designed to select conditions that position the red cocrystal stability zone as close to the stoichiometric reactions compositions that exist along the dashed line. The reaction depicted on the left is more likely to produce a cocrystal than the reaction on the right.

Kofler Hot Stage Screening and Characterization

Kofler screening is a process of generating a melt of the API and coformer on a slide. The two materials are carefully mixed at an interface where cocrystal formation can take place. In the reaction shown above two cocrystals of different stoichiometry have formed.

Hot stage methods are a very effective way to characterize some cocrystal systems as well as probe cocrystal polymorphism. Renovo has designed and built custom hot bench equipment and developed proprietary methods for characterizing cocrystals from the melt

Renovo does not use methods culled from the literature...

Renovo uses a custom designed and manufactured high throughput screening platform

The image above shows pieces of Renovo's 'take-apart' wet milling reactor plates. This is only a small sampling of Renovo's proprietary collection of custom manufactured screening equipment. With in-house CNC milling capabilities Renovo has created an extensive set of custom tools and modified equipment that is optimized to assemble and nucleate novel multi-component crystal forms. Renovo uses a combination of high-througput and low-throughput approaches to create an optimal solid form screening approach for each API. These methods and associated equipment are proprietary and unpublished.

A new approach to cocrystal formulation

Cocrystals can fail to perform without a suitable formulation

Pharmaceutical drug discovery efforts have yielded compounds with higher efficacy, but many of these compounds also have low water solubility. This can significantly hinder the drug product performance. Cocrystals can improve the water solubility of a drug compound, but in order to take full advantage of the improved cocrystal properties, a suitable cocrystal formulation is required. The research in this area being conducted by Renovo makes us the preferred partner for developing effective cocrystal formulations.

Spring and Parachute based drug delivery for cocrystals

A supersaturating drug delivery system for highly soluble cocrystals of poorly soluble drugs

The discovery and characterization of cocrystals has become a well developed field in the last decade and the potential for these new crystalline forms to improve physical properties of an API has been well documented. However, published approaches to delivering cocrystals in oral formulations highlights a critical gap that remains between the potential benefits that a cocrystal can provide and the knowledge required for the successful application of this technology. The research efforts at Renovo are filling this gap by creating a cocrystal drug delivery system that can be applied to the formulation of high solubility cocrystals of poorly soluble drugs.

Cocrystals create supersaturating systems

There are a variety of different formulation approaches available to improve the bioavailability of poorly soluble APIs. The majority of these approaches can be classified as supersaturating drug delivery systems. Cocrystals can have high kinetic solubility and create supersaturated solutions. With proper formulation cocrystals represent an alternative to traditional methods of increasing bioavailability.

A supersaturated system is one in which the concentration of the API in solution is higher than the solubility of the least soluble API crystal form that crystallizes under those conditions. A supersaturated system is not at equilibrium and without proper formulation the API can precipitate, resulting in lower solution concentrations.

Cocrystal solid form selection requires unique criteria

Cocrystals can have unique attributes that can make the selection of the most appropriate cocrystal for development more difficult. Renovo has the expertise and experience needed to understand complex cocrystal dissolution behavior.

For example, intuitively a cocrystal with a higher solubility would be preferred, but often this is not the case. Rapid cocrystal dissolution can generate supersaturation levels that generate high nucleation and growth rates of the least soluble API crystal form. As shown in the figure above, a cocrystal with 22X higher solubility can have a lower effective solution concentration over time compared to a cocrystal with only 4X higher solubility.

Inhibiting crystallization after cocrystal dissolution can improve the performance

Crystallization inhibitors are used to create a formulation that extends the metastable zone width of the supersaturation event. The inhibition of API crystallization in combination with generating the highest effective initial supersaturation levels will result in an extended period of the supersaturated state, which in turn will lead to higher plasma levels.

Achieving supersaturation may require excipients

A two phase approach to creating a supersaturating cocrystal drug delivery system

The innovative aspect of Renovo's approach to cocrystal formulation is the identification and control over the supersaturation levels achieved during cocrystal dissolution. This is achieved by directly manipulating the cocrystal solubility using pharmaceutically acceptable excipients that are incorporated into a supersaturating drug delivery system. By using these excipients to tune a system for optimal performance, the highest practical supersaturated solution concentrations can be achieved while avoiding the 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”.

Cocrystal dissolution experimental considerations

The methods used to characterize the dissolution profile of a polymorph or salt under sink conditions will be very different from the techniques required to accurately evaluate the dissolution profile of a supersaturating cocrystal. For example, the intrinsic dissolution profile under standard conditions will often suggest that the cocrystal of an API has essentially the same dissolution rate as the API, but this is rarely true. It is common for the cocrystal to immediately form a thin layer of precipitated API on the disk surface when exposed to aqueous media (causing the perceived solubility equal to the API), which often goes undetected in post-experiment XRPD or other spectroscopic analysis because the layer is so thin. A more effective determination of cocrystal utility can be obtained using well designed non-sink powder dissolution experiments. Renovo has the experience necessary to design, perform, and analyze powder dissolution profiles of your cocrystal in order to determine the potential utility of the cocrystal.

Renovo can be a valuable partner in your efforts to create a cocrystal drug delivery system

There is a considerable amount of effort in the pharmaceutical field being directed towards the use of cocrystals as pharmaceutical dosage forms, but without a rational and general approach to the successful formulation and delivery of cocrystals, the potential for taking advantage of the improved cocrystal properties and making meaningful, improved pharmaceutical products may not be realized in many cases. Renovo has the experience and knowledge to make cocrystals into a significant enabling technology that can be used to realize the full therapeutic potential of an API.

Cocrystals may need formulation assistance to perform

Formulation of a Danazol Cocrystal with Controlled Supersaturation

S.L. Childs, et al., Molecular Pharmaceutics, 2013, 10 (8), 3112–3127

Cocrystals have become an established approach for creating crystalline solids with improved solubility, but there has been a critical gap in the knowledge required to translate that potential into formulations that can effectively compete with the current technologies used to formulate poorly soluble APIs. Results recently published by Renovo demonstrate that in order to take advantage of a cocrystal’s potential solubility improvement, it is necessary to create a formulated environment that enables that potential to be realized.

The current approach to in-vivo evaluation of cocrystals both academically and industrially has focused on isolating and testing the ability of the inherent cocrystal properties to improve bioavailability by deliberately excluding any additional formulation in favor of neat aqueous suspensions of the crystalline materials or loading neat crystalline material into capsules. This approach assumes that the inherent properties of the cocrystal form are all that is necessary to improve bioavailability, but results from the published danazol:vanillin cocrystal system suggest that it is essential to consider both crystal form and formulation simultaneously in order to fully utilize the improved cocrystal properties.

Our internal research demonstrates that without an enabling formulation the true potential of cocrystals of poorly soluble drugs is not achieved. The innovative aspects of Renovo’s approach to cocrystal formulation are focused on the methods used to maintain control over supersaturation levels and inhibit precipitation. Renovo believes that this cocrystal formulation approach can be applied to a broad range of dosage forms. For example we believe that cocrystals can often successfully compete with amorphous dispersions. A dispersion may initially appear to perform better than an unformulated cocrystal, but this may be an incomplete result!

Download manuscript PDF for free here

Fiber-optic spectrometer increases dissolution throughput

Multi-channel UV-vis with dip probes

Renovo uses a Pion in situ fiber optic UV monitoring system to rapidly characterize powder dissolution experiments. Dr. Childs completed the Fiber-Optic Advanced Training Course and is experienced with the use of this instrument.

Determination of LLPS

The concentration where liquid-liquid phase separation (LLPS) occurs can be determined by monitoring a non-absorbing wavelength and observing when light scattering microscopic droplets are formed.

API flux through an artificial membrane

This is a two chambered cell separated by an artificial membrane. The powder dissolution experiment is performed and monitored on one side and the rate of API diffusion across the membrane will reflect the effective supersaturation levels.

Multi-channel means parallel experiments

Testing multiple conditions simultaneously allows for greater exploration of conditions that will allow the cocrystal to perform to its full potential.

R&D

R&D at Renovo is a top priority

Our services are a direct result of our continuous R&D efforts