AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Cocrystals

 

Abstract Image

Cocrystals are becoming popular in the pharmaceutical industry as they can offer advantages over the use of the active pharmaceutical ingredient (API) by itself.
  • 1.Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950
  • 2.Shan, N.; Zaworotko, M. Drug Discovery Today 2008, 13, 440
  • 3.Qiao, N.; Li, M.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Int. J. Pharm. 2011, 419, 1
Pharmaceutical companies now consider the possibilities of cocrystals early in the development of their APIs. Similar to salts, the investigation of cocrystals can multiply the number and diversity of solid form choices and thus increases the probability of identifying suitable development candidates for APIs that present solubility, bioavailability,(4) or stability issues.
4.Blagden, N.; de Matas, M.; Gavan, P.; York, P. Adv. Drug Delivery Rev. 2007, 59, 617
As a means to improve unit operations such as purification or racemic resolution,(5) the application of cocrystal intermediates might also be envisaged. Publications citing such applications are not numerous. Examples are thus far limited to the extraction of cinnamic acid from a fermentation broth(6) and to the feasibility of purifying synthetic mixtures by forming a cocrystal of the major component(7) or a cocrystal of the impurity.(8)

5.(a) Kovari, Z.; Bocskei, Z.; Kassai, C.; Fogassy, E.; Kozma, D. Chirality 2004, 16, S23

(b) Roy, B. N.; Singh, G. P.; Srivastava, D.; Jadhav, H. S.; Saini, M. B.; Aher, U. P. Org. Process Res. Dev. 2009, 13, 450

 

Active pharmaceutical ingredients (APIs) are frequently delivered to the patient in the solid state as part of such dosage forms as tablets, capsules, etc.In this context the ability to deliver the drug to the patient in a safe, efficacious and cost-effective way depends largely on the physicochemical properties of the APIs in the solid state, and accordingly one of the challenging tasks in the pharmaceutical industry is to design pharmaceutical solid materials with specific physicochemical properties. In the last years, the formation of pharmaceutical cocrystals has gained an increased interest as a means of optimizing the physicochemical properties of solid dosage forms. Apart from potential improvements in solubility, dissolution rate, bioavailability and physical stability, pharmaceutical cocrystals frequently enhance other essential properties of the APIs such as hygroscopicity, chemical stability, compressability and flowability.

 

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.

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.

 

Screening active pharmaceutical ingredients (APIs) to investigate new solid forms, including polymorphs, salts, cocrystals, and amorphous dispersions, is a common practice for new chemical entities (NCEs) and marketed products. New solid forms will have different properties, such as solubility, crystallinity stability, and bioavailabilty, which can aid in the development of early formulations and later-stage drug products. Different screens can be performed at different points in the development process, depending on the information needed and the goal of the screen.  early development may include a small polymorph, salt, cocrystal, or amorphous dispersion screen. Later in development, new properties may be needed; therefore, an extended screen may be implemented to produce a modified and improved formulation. All of these screens work together to support the formulation goals to produce a product that has acceptable performance.
To date, no cocrystalline drug products appear to be on the market, although there is no doubt that cocrystals are present in pharmaceutical drug pipelines and it is only a matter of time before this imagination becomes a reality.

One can clearly see a place for cocrystals within the pharmaceutical market. On the basis of the limited examples available, some general comments can be made on the physicochemical properties of cocrystals. Melting points are altered for most cocrystals, with approximately 51% resulting in melting points between those of the API and coformer and 39% resulting in lower melting points. Correlations with other parameters, such as solubility, are limited and will be complex due to the multicomponent nature of the cocrystals. In many cases, improved stability, such as resistance to hydrate formation, has been shown for cocrystals. However, general trends are not evident and each system needs to be evaluated to determine if improvements are obtained. Improved solubility for poorly soluble compounds has been achieved using cocrystals. Limited studies suggest that salts will provide a larger increase in solubility if they are available. For poorly soluble neutral compounds, cocrystals are a very feasible approach to improving solubility. Cocrystals can provide higher and lower dissolution rates compared to the API. Dissociation is an important consideration in analyzing data from these experiments. It was shown that significant increases in bioavailability are possible with cocrystals, even when dissociation of the cocrystal is suspected based on in vitro studies.

Other aspects of development, such as polymorphism and scale-up, will need to be examined for cocrystals. Processes to produce cocrystals on a large scale will likely require different approaches, such as those based on ternary solubility phase diagrams. Cocrystals will provide additional options for IP, regulatory, and lifecycle management for new and old drugs and will provide additional challenges as they continue through the development process.

The primary focus of this article is centered on highlighting cases where the physicochemical properties of an API have been adjusted through the formation of API-based cocrystals. The properties and questions are

Melting point: Does the thermal behavior (melting point) of a cocrystal change with respect to the individual components and can the melting points be estimated within a series of cocrystals?
Stability: Can physical and chemical stability be enhanced upon cocrystallization of an API?
Solubility: Can the solubility of an API be altered by modifying it into a cocrystal?
Dissolution: Are dissolution rates improved by cocrystalline compounds in comparison to the individual APIs?
Bioavailability: Can the bioavailability of an API be improved using cocrystals?

 

The definition of a cocrystal has been debated in the crystallography field. The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio, where each component is defined as either an atom, ion, or molecule. However, this definition encompasses many types of compounds, including hydrates, solvates and clathrates, which represent the basic principle of host-guest chemistry. Hundreds of cocrystallization are reported annually.

Cocrystals are crystalline materials composed of two or more molecules held together within the same crystal lattice. Cocrystallisation is significant in the pharmaceutical industry, where drug molecules are screened for cocrystal formation in order to improve their solubility, stability and bioavailability. This has the added advantage of increasing the number of crystal forms that can be considered for drug formulation while simultaneously maximising patent protection.

Pharmaceutical cocrystals could be used to improve the physicochemical properties of active pharmaceutical ingredients. Here, a practical solid form screen approach to identify pharmaceutical cocrystals in the early development stage is proposed. This approach first used a cogrinding screen to identify potential cocrystal former leads that could formcocrystals with the compound of interest, followed by a solvent-based screen to identify, evaluate, and generate the cocrystal candidates. This approach not only allows fast identification of the cocrystal candidates but also provides insights on their scalability. Using this approach for the development drug candidate, a glutaric acid cocrystal was identified that provided an improved intrinsic dissolution rate in comparison to that of the free form, and therefore this cocrystal is potentially a better solid form for development. The effects of solvents and structures of cocrystal formers on the cocrystal formation and the rationales for this approach are also discussed.

Pharmaceutical cocrystals are well-defined crystalline solids generated from active pharmaceutical ingredients (API) and cocrystal formers (CCF). In recent years, identification and development of pharmaceutical cocrystals gained increasing interest in the pharmaceutical industry.The approach of cocrystal formation can diversify the solid form choices and increase the chances to identify suitable development candidates, especially for APIs with no crystalline form, nonionizable functional groups, or low pKa values (to maintain as a stable salt). Examples of pharmaceutical cocrystals have been demonstrated in the literature to provide improved properties such as physical stability, dissolution rate, and solubility, and thus they can be used as an alternative solid dosage form for an API.

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Polymorph screens focus on finding new forms of an API and can include unsolvated, solvated, hydrated, and even amorphous materials. Salt, cocrystal, and amorphous dispersion screens use additional materials, such as counterions, cocrystal formers, and polymers, respectively. For all solid forms, small screens in early development may lead to medium size screens for phase II or III trials and a more comprehensive screen near launch. It should be noted that, once a new salt or cocrystal is targeted for development, a polymorph screen should be performed on that material to determine the possible forms, the thermodynamically stable form, and how this new form best fits within the development plan.

 

GLOSSARY

Co-crystals: Crystalline materials composed of two or more molecules within the same
crystal lattice.

Polymorphs: Different crystalline forms of the same drug substance. This may include
solvation or hydration products (also known as pseudopolymorphs) and amorphous forms. Per
the current regulatory scheme, different polymorphic forms are considered the same active
ingredients. (See Guidance for Industry: ANDAs: Pharmaceutical Solid Polymorphism:
Chemistry, Manufacturing, and Controls Information, July 2007.)

Salts: Any of numerous compounds that result from replacement of part or all of the acid
hydrogen of an acid by a metal or a radical acting like a metal: an ionic or electrovalent
crystalline compound. Per the current regulatory scheme, different salt forms of the same active
moiety are considered different active ingredients. (See 21 CFR 314.108 and 21 CFR 320.1(c).)

History

The first reported cocrystal, quinhydrone, was studied by Friedrich Wöhler in 1844. Quinhydrone is a cocrystal of quinone and hydroquinone (knowns archaically as quinol). He found that this material was made up of a 1:1 molar combination of the components. Quinhydrone was analyzed by numerous groups over the next decade and several related cocrystals were made from halogenated quinones.[1]

Many cocrystals discovered in the late 1800s and early 1900s were reported in Organische Molekulverbindungen, published by Paul Pfeiffer in 1922.[1] This book separated the cocrystals into two categories; those made of inorganic:organic components, and those made only of organic components. The inorganic:organic cocrystals include organic molecules cocrystallized with alkali and alkaline earth salts, mineral acids, and halogens as in the case of the halogenated quinones. A majority of the organic:organic cocrystals contained aromatic compounds, with a significant fraction containing di- or trinitro aromatic compounds. The existence of several cocrystals containing eucalyptol, a compound which has no aromatic groups, was an important finding which taught scientists that pi stacking is not necessary for the formation of cocrystals.[1]

Cocrystals continued to be discovered throughout the 1900s. Some were discovered by chance and others by screening techniques. Knowledge of the intermolecular interactions and their effects on crystal packing allowed for the engineering of cocrystals with desired physical and chemical properties. In the last decade there has been an enhanced interest in cocrystal research, primarily due to applications in the pharmaceutical industry.[2]

Cocrystals represent about 0.5% of the crystal structures archived in the Cambridge Structural Database (CSD).[2] However, the study of cocrystals has a long history spanning more than 160 years. They have found use in a number of industries, including pharmaceutical, textile, paper, chemical processing, photographic, propellant, and electronic.[1]

Definition

The meaning of the term “cocrystal” is subject of disagreement. One definition states that a cocrystal is a crystalline structure composed of at least two components, where the components may be atoms, ions or molecules.[1] This definition is sometimes extended to specify that the components be solid in their pure forms at ambient conditions.[3]However, it has been argued that this separation based on ambient phase is arbitrary.[4] A more inclusive definition is that cocrystals “consist of two or more components that form a unique crystalline structure having unique properties.”[5] Due to variation in the use of the term, structures such as solvates and clathrates may or may not be considered cocrystals in a given situation. It should be noted that the difference between a crystalline salt and a cocrystal lies merely in the transfer of a proton. The transfer of protons from one component to another in a crystal is dependent on the environment. For this reason, crystalline salts and cocrystals may be thought of as two ends of a proton transfer spectrum, where the salt has completed the proton transfer at one end and an absence of proton transfer exists for cocrystals at the other end.[5]

Definitions of a Cocrystal

Even though there are limitations with the cocrystal definitions currently found in the literature, we do not see it necessary to complicate the existing debate by generating yet another definition for what constitutes a cocrystal. In this review, the cocrystalline examples presented herein will possess the following criteria:

(1) An API, neutral (below), or ionic form  or a zwitterion, along with a neutral coformer, held together through noncovalent, freely reversible interactions,

Figure 2

Possible multicomponent systems: cocrystals, salt cocrystals, and salts along with their respective solvate/hydrate forms.

(2) a coformer, which may or may not be pharmaceutically acceptable,

(3) and at least one measured physicochemical property.

 

Properties

A schematic for the determination of melting point binary phase diagrams from thermal microscopy.

The components interact via non-covalent interactions such as hydrogen bondingionic interactions, van der Waals interactions and Π-interactions. The intermolecular interactions and resulting crystal structures can generate physical and chemical properties that differ from the properties of the individual components.[6] Such properties include melting point, solubility, chemical stability, and mechanical properties. Some cocrystals have been observed to exist as polymorphs, which may display different physical properties depending on the form of the crystal.[6]

Phase diagrams determined from the “contact method” of thermal microscopy is valuable in the detection of cocrystals.[1] The construction of these phase diagrams is made possible due to the change in melting point upon cocrystallization. Two crystalline substances are deposited on either side of a microscope slide and are sequentially melted and resolidified. This process creates thin films of each substance with a contact zone in the middle. A melting point phase diagram may be constructed by slow heating of the slide under a microscope and observation of the melting points of the various portions of the slide. For a simple binary phase diagram, if one eutectic point is observed then the substances do not form a cocrystal. If two eutectic points are observed, then the composition between these two points corresponds to the cocrystal.

Pharmaceutical co-crystals can be defined as crystalline materials comprised of an API and one or more unique co-crystal formers, which are solids at room temperature.

Co-crystals can be constructed through several types of interaction, including hydrogen bonding, p stacking, and vander Waals forces. Solvates and hydrates of the API are not considered to be co-crystals by this definition. However, co-crystals may include one or more solvent/water molecules in the crystal lattice. Co-crystals often rely on hydrogen-bonded assemblies between neutral molecules of API and other component. For nonionizable compounds co-crystals enhance pharmaceutical properties by modification of chemical stability, moisture uptake, mechanical behaviour, solubility, dissolution rate and bioavailability.

ADVANTAGES OF CO-CRYSTALS

Co-crystals having advantages like stable crystalline form (as compared to amorphous solids), no need to make or break covalent bonds, theoretical capability of all types of API molecules (weakly ionizable/non-ionizable) to form co-crystals, the existence of numerous potential counter-molecules (food additives, preservatives, pharmaceutical excipients, and other APIs), the only solid form that is designable via crystal engineering patentable expanding IP portfolios and can be produced using solid-state synthesis green technologies high yield, no solvent or by-products.

 

Production and characterization

Production

There are a multitude of synthetic strategies that are available to prepare cocrystals. However, it may be difficult to prepare single cocrystals for X-ray diffraction, as it has been known to take up to 6 months to prepare these materials.[5]

Cocrystals are typically generated through slow evaporation of solutions of the two components. This approach has been successful with molecules of complimentary hydrogen bonding properties, in which case cocrystallization is likely to be thermodynamically favored.[7]

A multitude of other methods exist in order to produce cocrystals. Crystallizing with a molar excess of one cocrystal former may produce a cocrystal by a decrease in solubility of that one component. Another method to synthesize cocrystals is to conduct the crystallization in a slurry. As with any crystallization, solvent considerations are important. Changing the solvent will change the intermolecular interactions and possibly lead to cocrystal formation. Also, by changing the solvent, phase considerations may be utilized. The role of a solvent in nucleation of cocrystals remains poorly understood but critical in order to obtain a cocrystal from solution.[7]

Cooling molten mixture of cocrystal formers often affords cocrystals. Seeding can be useful.[6] Another approach that exploits phase change is sublimation which often formshydrates.[8]

Grinding, both neat and liquid-assisted, is employed to produce cocrystal, e.g., using a mortar and pestle, using a ball mill, or using a vibratory mill. In liquid-assisted grinding, or kneading, a small or substoichiometric amount of liquid (solvent) is added to the grinding mixture. This method was developed in order to increase the rate of cocrystal formation, but has advantages over neat grinding such as increased yield, ability to control polymorph production, better product crystallinity, and applies to a significantly larger scope of cocrystal formers.[9] and nucleation through seeding.[8]

Supercritical fluids (SCF’s) serve as a media for growing cocrystals. Crystal growth be achieved due to unique properties of SCFs by using different supercritical fluid properties: supercritical CO2 solvent power, anti-solvent effect and its atomization enhancement.

Using intermediate phases to synthesize solid-state compounds are also employed. Through the use of a hydrate or an amorphous phase as an intermediate during synthesis in a solid-state route has proven successful in forming a cocrystal. Also, the use of a metastable polymorphic form of one cocrystal former can be employed. In this method, the metastable form acts as an unstable intermediate on the nucleation pathway to a cocrystal. As always, a clear connection between pairwise components of the cocrystal are needed in addition to the thermodynamic requirements in order to form these compounds.[6]

Importantly, the phase that is obtained is independent of the synthetic methodology used. It may seem facile to synthesize these materials, but on the contrary the synthesis is far from routine.[7]

choosing

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Example flowchart for choosing a cocrystal candidate.

solubility

One of the main reasons to investigate cocrystals is to increase the solubility of a poorly soluble compound. For neutral molecules, cocrystals can certainly expand the solid forms possible for development. For a free acid or free base, both salts and cocrystals can be used to improve the solubility; however, it is not always straightforward to determine whether a salt or a cocrystal has been formed and a variety of techniques may be needed to understand the system.

Characterization

Cocrystals may be characterized in a wide variety of ways. Powder X-Ray diffraction proves to be the most commonly used method in order to characterize cocrystals. It is easily seen that a unique compound is formed and if it could possibly be a cocrystal or not owing to each compound having its own distinct powder diffractogram.[3] Single-crystal X-ray diffraction may prove difficult on some cocrystals, especially those formed through grinding, as this method more often than not provides powders. However, these forms may be formed often through other methodologies in order to afford single crystals.[9]

Aside from common spectroscopic methods such as FT-IR and Raman spectroscopy, solid state NMR spectroscopy allows differentiation of chiral and racemic cocrystals of similar structure.[9]

Other physical methods of characterization may be employed. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) are two commonly used methods in order to determine melting points, phase transitions, and enthalpic factors which can be compared to each individual cocrystal former.

Cocrystal Characterization

c. Childs S. L.; Stahly G. P.; Park A. Mol. Pharmaceutics 2007, 4, 323–338.[PubMed]

  • Newman A. W.; Childs S. L.; Cowans B. A.Salt Cocrystal Form Selection, InPreclinical Development Handbook; John Wiley and Sons: Hoboken, 2008; pp 455−481.
  • Li Z. J.; Abramov Y.; Bordner J.; Leonard J.; Medek A.; Trask A. V. J. Am. Chem. Soc. 2006, 128, 8199–8210. [PubMed]
  • Aakeröy C. B.; Salmon D. J.; Smith M. M.; Desper J. Cryst. Growth Des.2006, 6, 1033–1042.
  • a. Aakeröy C. B.; Hussain I.; Desper J. Cryst. Growth Des. 2006, 6, 474–480.

Single crystal X-ray diffraction is the preferred characterization technique in determining whether a cocrystalline material has been generated; however, suitable X-ray quality crystals cannot always be produced. Additionally, even if single crystals can be grown of sufficient size and quality, the exact location of the hydrogen atom (determination if proton-transfer has occurred from the acid to the base or not) may be ambiguous. Thus, it is advantageous to utilize a variety of solid-state, spectroscopic techniques (Raman, infrared, and solid-state NMR) when attempting to characterize potentially new cocrystalline materials.

Such an exercise was carried out when single-crystal X-ray crystallography and 15N solid-state cross-polarization magic angle spinning (CPMAS) NMR spectroscopy were used to complement one another in the determination of hydrogen bonding interactions and the extent of proton-transfer between a heterocyclic-containing API and a variety of dicarboxylic acids.(28) Three acid−base complexes were obtained and characterized: a sesquisuccinate, a dimalonate, and a dimaleate. Through single-crystal X-ray analysis, measured hydrogen bond distances were used to characterize the materials as one cocrystal (sesquisuccinate), one mixed ionic and zwitterionic complex (dimalonate), and one disalt (dimaleate). These results were confirmed by comparing the 15N chemical shifts of each species to those of the free base. Small shifts, in comparison to the free base, were observed for the sesquisuccinate cocrystal, while the largest shifts, due to complete protonation, were seen from the dimaleate salt. In addition, short contact time CPMAS NMR experiments were used to further characterize the dimalonate and dimaleate complexes as a mixed ionic species and a disalt. For example, if a nitrogen atom had a proton attached to it, then a signal would appear; thus the disalt (dimaleate) displayed two additional peaks in comparison to the free base, while the mixed ionic species (dimalonate) only showed one new peak. The results from the 15N solid-state CPMAS NMR spectroscopy along with single-crystal X-ray crystallography proved sufficient to successfully identify each new form as either a cocrystal, salt, or mixed ionic complex.

Infrared spectroscopy can be a very powerful tool in detecting cocrystal formation, especially when a carboxylic acid is used as a coformer and/or when a neutral O−H···N hydrogen bond is formed between an acid and a base. Distinct differences, within the IR spectra, can be observed between a neutral carboxylic acid moiety and a carboxylate anion. A neutral carboxylate (-COOH) displays a strong C=O stretching band around 1700 cm−1 and a weaker C−O stretch around 1200 cm−1, while a carboxylate anion (-COO), due to resonance, displays a single C−O stretch in the fingerprint region of 1000−1400 cm−1. Additionally, if a neutral intermolecular O−H···N hydrogen bond has formed between the components, then two broad stretches around 2450 and 1950 cm−1 will be observed. Observations about the state of the carboxylic moiety (neutral or ionic) can also be verified through measuring the C−O and C=O bond distances from the single-crystal X-ray data. A typical C=O bond distance is around 1.2 Å, while the C−O bond distance is around 1.3 Å; however, if deprotonation has occurred then the resonance stabilized C−O bond distances will be very similar.

Outlined above are a number of different characterization techniques used to help distinguish between cocrystals and salts, and it should be noted that in some cases differentiation between the two may be difficult. It should also be pointed out that although salts and cocrystals often possess different properties (see sections on stability () and solubility ()), these issues from a development standpoint may not be influential as long as the process can be monitored and closely controlled. However, for intellectual property (IP) rights and regulatory issues, differentiating between a cocrystal and a salt can be important, as discussed in .

DESIGN OF CO-CRYSTALS

The crystal engineering experiment typically involves the Cambridge Structural Database (CSD) survey followed by the experimental work. Co-crystals designed on the principal of the supramolecular synthesis; it provides a powerful approach for proactive discovery of novel pharmaceutical solid phases. Co-crystals consist of multiple components in given stoichiometric ratio, where different molecular species interact by hydrogen bonding and by non-hydrogen bonding.

The use of hydrogen bonding rules, synthons and graph sets may assist in the design and analysis of co-crystal systems. In general though, prediction of whether co-crystallization will occur is not yet possible and must, at present, be answered empirically. Co-crystal formation may be rationalised by consideration of the hydrogen bond donors and acceptors of the materials that are to be co-crystallized and how they might interact. Following the extensive examination of preferential packing preferences and hydrogen bond patterns in a number of organic crystals, Etter and co-workers proposed the guidelines to facilitate the deliberate design of hydrogen-bonded solids. All good proton donors and acceptors are used in hydrogen bonding, six-membered ring intermolecular hydrogen bonds form in preference to intermolecular hydrogen bonds, the best proton donor and acceptor remaining after intermolecular hydrogen-bond formation will form intermolecular hydrogen bonds to one another (but not all acceptors will necessarily interact with donors). These observations help to address the issue of competing hydrogen bond assemblies observed when using a particular cocrystallising agent.

A detailed understanding of the supramolecular chemistry of the functional groups present in a given molecule is the prerequisite for designing the co-crystals because it facilitates the selection of the suitable co-crystal former. Supramoecular synthons that can occur in common functional group in order to design new co-crystals and certain functional groups such as carboxylic acids, amides and alcohols are particularly amenable to formation of supramolecular heterosynthon. The strong hydrogen bond includes (N-H—O), (O-H—O), (-N-H—N,) and (O-H—N). The weak hydrogen bonds involves the −C-H—O and C-H—O=C.

Applications

Cocrystal engineering is relevant to production of energetic materials, pharmaceuticals, and other compounds. Of these, the most widely studied and used application is in drug development and more specifically, the formation, design, and implementation of active pharmaceutical ingredients, or API’s. Changing the structure and composition of the API can greatly influence the bioavailability of a drug.[7] The engineering of cocrystals takes advantage of the specific properties of each component to make the most favorable conditions for solubility that could ultimately enhance the bioavailability of the drug. The principal idea is to develop superior physico-chemical properties of the API while holding the properties of the drug molecule itself constant.[10]

Intellectual Property (IP) and Lifecycle Management

  • Trask A. V. Mol. Pharm. 2007, 4, 301–309. [PubMed]
  • Thayer A. M. Chem. Eng. News 2007, 85, 17–30.

Patents have become a critical element of drug development, especially when covering solid forms. There have been limited reports on cocrystals and IP, but more information on this area is expected as the field grows. Pharmaceutical patents can cover a number of different areas, including composition of matter (molecular structure, solid form, or formulation), method of use (medical indication), and manufacturing processes. In order for an invention to qualify for patent coverage, it must satisfy three criteria: novelty, utility, and nonobviousness. For solid form patent applications directed to pharmaceuticals in general, utility is not usually problematic, and the examples in this paper readily show examples of utility of new cocrystals above and beyond the therapeutic effect of the API. For a solid form to be novel, it cannot appear in the prior art either expressly or inherently. For most pharmaceutical cocrystals, prior art is limited since the coformer would likely not be published in connection with the crystallization of the API. This lack of prior art is an advantage from the IP perspective. The third area is being nonobvious, which may be viewed, in at least some circumstances, as correlating with predictability. Crystal engineering is certainly an advantage when trying to decide on possible coformers, but there is no guarantee that a cocrystal will form. Computational analyses are also not able to reliably predict the structure or properties of cocrystals at this point in time, which adds to the nonobvious nature of solid forms in general and especially cocrystals.

Cocrystals represent a broad patent space since there is a large number of coformers available based on the possible compounds in the EAFUS (Everything Added to Food in the US) and GRAS (Generally Regarded as Safe) lists. However, because of the lack of predictability in the field, it is expected that in many circumstances patent coverage will be narrow.

Cocrystals can also play a role in lifecycle management. Lifecycle management can involve drug product improvements along with new solid forms. Early in the development process, chemical structures are patented and additional IP protection can be obtained by patenting different solid forms throughout development. If an approved drug product contains a new patented solid form, especially where the solid form offers a commercial advantage over the original form, the solid form patent might provide meaningful IP protection after the expiration of the original patent. However, a solid form that was not found by the innovator, but was found and patented by a competitor, could significantly alter this strategy. Cocrystal screens for potential blockbuster drugs could end up being very large in order to protect, not only the cocrystals found, but also any polymorphs, hydrates, solvates, or other solid forms of the individual cocrystals.

From a regulatory point of view for generic products, cocrystals may present an interesting option. Currently, when generic pharmaceutical companies use polymorphs and hydrates as alternatives to ethical drugs, they file Abbreviated New Drug Applications (ANDAs), which requires the submission of minimal bioavailability and clinical data and does not require proving safety or efficacy. New salts of an API, however, use a slightly different regulatory pathway, a so-called 505(b)(2) application, and require more testing and clinical data than an ANDA submission. The classification of cocrystals as a generic has not yet been addressed. Cocrystals contain nonionic interactions like hydrates, but they also contain substances with possible toxicity issues, similar to salts. The decision on how to regulate cocrystals for generic products may affect their use in the generic industry.

Cocrystals will raise IP and regulatory questions as more of these compounds are developed, moved later into development, and eventually marketed. As with any solid form, they will offer their own challenges and many issues will need to be dealt with on a case by case basis.

Pharmaceuticals

Cocrystal engineering has become of such great importance in the field of pharmaceuticals that a particular subdivision of multicomponent cocrystals has been given the term pharmaceutical cocrystals to refer to a solid cocrystal former component and a molecular or ionic API. However, other classifications also exist when one or more of the components are not in solid form under ambient conditions. For example, if one component is a liquid under ambient conditions, the cocrystal might actually be deemed a cocrystal solvate as discussed previously. The physical states of the individual components under ambient conditions is the only source of division among these classifications. The classification naming scheme of the cocrystals might seem to be of little importance to the cocrystal itself, but in the categorization lies significant information regarding the physical properties, such as solubility and melting point, and the stability of API’s.[7]

The objective of pharmaceutical cocrystals is have properties that differ from that expected of the pure API’s without making and/or breaking covalent bonds.[11] Among the earliest pharmaceutical cocrystals reported are of sulfonamides.[10] The area of pharmaceutical cocrystals has thus increased on the basis of interactions between API’s and cocrystal formers. Most commonly, API’s have hydrogen-bonding capability at their exterior which makes them more susceptible to polymorphism, especially in the case of cocrystal solvates which can be known to have different polymorphic forms. Such a case is in the drug sulfathiazole, a common oral and topical antimicrobial,which has over a hundred different solvates. It is thus important in the field of pharmaceuticals to screen for every polymorphic form of a cocrystal before it is considered as a realistic improvement to the existing API. Pharmaceutical cocrystal formation can also be driven by multiple functional groups on the API, which introduces the possibility of binary, ternary, and higher ordered cocrystal forms.[12] Nevertheless, the cocrystal former is used to optimize the properties of the API but can also be used solely in the isolation and/or purification of the API, such as a separating enantiomers from each other, as well and removed preceding the production of the drug.[7]

It is with reasoning that the physical properties of pharmaceutical cocrystals could then ultimately change with varying amounts and concentrations of the individual components. One of the most important properties to change with varying the concentrations of the components is solubility.[11] It has been shown that if the stability of the components is less than the cocrystal formed between them, then the solubility of the cocrystal will be lower than the pure combination of the individual constituents. If the solubility of the cocrystal is lower, this means that there exists a driving force for the cocrystallization to occur.[3] Even more important for pharmaceutical applications is the ability to alter the stability to hydration and bioavailability of the API with cocrystal formation, which has huge implications on drug development. The cocrystal can increase or decrease such properties as melting point and stability to relative humidity compared to the pure API and therefore, must be studied on a case to case basis for their utilization in improving a pharmaceutical on the market.[10]

A screening procedure has been developed to help determine the formation of cocrystals from two components and the ability to improve the properties of the pure API. First, the solubilities of the individual compounds are determined. Secondly, the cocrystallization of the two components is evaluated. Finally, phase diagram screening and powderX-ray diffraction (PXRD) are further investigated to optimize conditions for cocrystallization of the components.[3] This procedure is still done to discover cocrystals of pharmaceutical interest including simple APIs, such as carbamazepine (CBZ), a common treatment for epilepsytrigeminal neuralgia, and bipolar disorder. CBZ has only one primary functional group involved in hydrogen bonding, which simplifies the possibilities of cocrystal formation that can greatly improve its low dissolution bioavailability.[7]

Another example of an API being studied would be that of Piracetam, or (2-oxo-1-pyrrolidinyl)acetamide, which is used to stimulate the central nervous system and thus, enhance learning and memory. Four polymorphs of Piracetam exist that involve hydrogen bonding of the carbonyl and primary amide. It is these same hydrogen bonding functional groups that interact with and enhance the cocrystallization of Piracetam with gentisic acid, a non-steroidal anti-inflammatory drug (NSAID), and with p-hydroxybenzoic acid, an isomer of the aspirin precursor salicylic acid.[7] No matter what the API is that is being researched, it is quite evident of the wide applicability and possibility for constant improvement in the realm of drug development, thus making it clear that the driving force of cocrystallization continues to consist of attempting to improve on the physical properties in which the existing cocrystals are lacking.[3][7]

Energetic materials

Two explosives HMX and CL-20 cocrystallized in a ratio 1:2 to form a hybrid explosive. This explosive had the same low sensitivity of HMX and nearly the same explosive power of CL-20. Physically mixing explosives creates a mixture that has the same sensitivity as the most sensitive component, which cocrystallisation overcomes.[13]

Crystal form can be crucial to the performance of a dosage form. This is especially true for compounds that have intrinsic barriers to drug delivery, such as low aqueous solubility, slow dissolution in gastrointestinal media, low permeability and first-pass metabolism. The nature of the physical form and formulation tends to exhibit the greatest effect on bioavailability parameters of water insoluble compounds that need to be given orally in high doses. An alternative approach available for the enhancement of drug solubility, dissolution and bioavailability is through the application of crystal engineering of co-crystals. The physicochemical properties of the active pharmaceutical ingredients and the bulk material properties can be modified, whilst maintaining the intrinsic activity of the drug molecule

METHODS OF PREPARATION OF CO-CRYSTALS

Portalone GC. First example of co-crystals of polymorphic maleic hydrazide. J Chem Crystallogr. 2004;34:609–12.

Aakeröy CB, Beatty AM, Helfrich BA, Nieuwenhuyzen M. Do polymorphic compounds make good cocrystallising agents? A structural case study that demonstrates the importance of synthon flexibility. Cryst Growth Des. 2003;3:159–65.
Zaworotko M. Polymorphism in co-crystals and pharmaceutical co-crystals.Florence: XX Congress of the International Union of Crystallography; 2005.
Blagden N, de Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev. 2007;59:617–30. [PubMed]
Mutalik S, Prambil A, Krishnan M, Achuta NU. Enhancement of dissolution rate and bioavailability of aceclofenac: A chitosan based solvent change approach. Int J Pharm. 2008;350:279–90. [PubMed]

Co-crystal formation described in the literature indicates the notoriously difficult situation these systems present with regard to preparation it has been known to take 6 months to prepare a single co-crystal of suitable quality for single X-ray diffraction analysis. This is partly because such a heteromeric system will only form if the non-covalent forces between two (or more) molecules are stronger than between the molecules in the corresponding homomeric crystals. Design strategies for co-crystal formation are still being researched and the mechanism of formation is far from being understood[36].

Co-crystals can be prepared by solvent and solid based methods. The solvent-based methods involve slurry conversion solvent evaporation, cooling crystallization and precipitation. The solid based methods involve net grinding; solvent-assisted grinding and sonication (applied to either to wet or dry solid mixtures) 80° to 85°.

Solution co-crystallization:

For solution co-crystallization, the two components must have similar solubility; otherwise the least soluble component will precipitate out exclusively. However similar solubility alone will not guarantee success. It has been suggested that it may be useful to consider polymorphic compounds, which exist in more than one crystalline form as co-crystallising components. If a molecular compound exists in several polymorphic forms it has demonstrated a structural flexibility and is not locked into a single type of crystalline lattice or packing mode. Thus, the chance of bringing such a molecule into a different packing arrangement in coexistence with another molecule is increased. Clearly polymorphism alone does not guarantee the functionality of a compound to act as a co-crystallising agent, whilst the ability of a molecule to participate in intermolecular interactions obviously plays a critical role.

Small-scale preparation has been described. Scale-up crystallization was performed in a 500 ml water-jacketed glass crystallization vessel. Temperature was maintained by a circulating water bath. A reflux column, digital thermometer, and overhead stirrer with a glass shaft and Teflon blade were attached to vessel ports. The drug and co-crystal former were added to a reaction vessel. The solids were dissolved in ethanol/methanol mixture and heated to 70° for 1 h under reflux. Temperature was decreased in 10° increments to induce precipitation in a stirred, unseeded system. Observe the appearance of the co-crystal. Literate to enhance solids recovery decrease the further temperature.

Grinding:

When preparing co-crystals, the product obtained from grinding is generally consistent with that obtained from solution. This may indicate that hydrogen-bond connectivity patterns are not idiosyncratic or determined by non-specific and unmanageable solvent effects or crystallization conditions. Nevertheless there are exceptions. Whilst many co-crystal materials can be prepared from both solution growth and solid-state grinding, some can only be obtained by solid-state grinding. An example is that in the co-crystallisation of 2,4,6-trinitrobenzoic acid and indole-3-acetic acid, different crystal forms were obtained from solution compared with grinding. Failure to form co-crystals by grinding may be due to an inability to generate suitable co-crystal arrangements rather than due to the stability of the initial phases. When co-crystal formation has been successful from solution, but not from grinding, solvent inclusion in stabilizing the supramolecular structure may be a factor. Although co-crystal formation by solid-state grinding has been established for some time and a late 19th century report is often cited as the earliest reference to such a procedure, the recent technique of adding small mounts of solvent during the grinding process has been shown to enhance the kinetics and facilitate co-crystal formation and as lead to increased interest of solid-state grinding as a method for co-crystal preparation.

Slurry conversion:

Slurry conversion experiments were conducted in different organic solvents and water. Solvent (100 or 200 ml) was added to the co-crystal (20 mg) and the resulting suspension was stirred at room temperature for some days. After some days, the solvent was decanted and the solid material was dried under a flow of nitrogen for 5 min. The remaining solids were then characterized using PXRD.

Antisolvent addition:

This is one of the methods for precipitation or recrystalization of the co-crystal former and active pharmaceutical ingredient. Solvents include buffers (pH) and organic solvents. For example preparation of co-crystals of aceclofenac using chitosan, in which chitosan solution was prepared by soaking chitosan in glacial acetic acid. A weighed amount of the drug was dispersed in chitosan solution by using high dispersion homogenizer. This dispersion was added to distilled water or sodium citrate solution to precipitate chitosan on drug.

 

case

It should be noted, however, that a second polymorph of a 1:1 cocrystal of carbamazepine/saccharin (Form II) was found using a polymer heteronuclei crystallization media, and the hydrogen bonding patterns for the two forms are shown in Figure below

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Polymorphic cocrystals of 1:1 carbamazepine/saccharin.

 

case

fluoxetine

 

For cocrystals of fluoxetine HCl, the aqueous solubility (called powder dissolution in the paper) was measured at various time points up to 120 min, and the solutions were analyzed by UV.Samples were sieved to obtain a particle size range of 53−150 μm. The fluoxetine hydrochloride solubility was 11.4 mg/mL. The benzoic acid cocrystal solubility was lower at 5.6 mg/mL and the fumaric cocrystal solubility was higher at 14.8 mg/mL. The succinic acid cocrystal had a peak solubility of 20.2 mg/mL after about 1 min, but then decreased to that of fluoxetine HCl based on the dissociation of the cocrystal to fluoxetine hydrochloride. This system exhibited higher and lower solubilities along with dissociation, making it a very interesting and complex set of cocrystal solubilities.

case

Three itraconazole cocrystals (succinic acid, l-malic acid, and l-tartaric acid) were compared with crystalline itraconazole (particles less than 10 μm) and commercial Sporanox beads (amorphous itraconazole).(61) Solutions of 0.1 N HCl were used and sampled over 500 min. The cocrystals all exhibited higher solubility than the crystalline itraconazole. The l-malic and l-tartaric acid cocrystals exhibited solubilities similar to that obtained for the Sporonax beads (approximately 7 × 10−4 M) and the succinic acid was lower (approximately 2 × 10−4 M). The cocrystalline forms achieved and sustained from 4- to 20-fold solubility increases over the crystalline itraconazole.

case

For norfloxacin, a cocrystal was formed with isonicotinamide and three salts were prepared (succinate, malonate, and maleate). Apparent aqueous solubility was measured after 72 h and the solution was analyzed by UV−vis; the form remaining at the end of the experiment was not reported. Norfloxacin apparent solubility was 0.21 mg/mL, whereas the apparent solubility ranged from 0.59 mg/mL for the isonicotinamide cocrystal to 3.9 mg/mL for the malonate salt and 9.8 mg/mL for the maleate salt. This resulted in a 3× increase in solubility for cocrystal and 20−45× increase for salts.

case

Devarakonda SN, Vyas K, Bommareddy SR, Padi PR, Raghupathy B. Aripiprazole co-crystals. 2007 WO/2007/092779.

Aripiprazole co-crystals, the present invention relates to co-crystals comprising aripiprazole and fumaric acid and processes for co-crystal preparation. Aripiprazole is a psychotropic drug useful for the treatment of schizophrenia and is the sixth, and most recent, of the second generation antipsychotic medications. It is available in the market under the brand name Abilify® in the form of tablets of 5, 10, 15, 20 and 30 mg strengths. Aripiprazole presents certain challenges for formulation as a rapid-onset dosage form, particularly as a rapid-onset oral dosage form. For example, aripiprazole has a very low solubility in aqueous media (being practically insoluble) and therefore is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract when administered orally, for example in tablet form. Towards this end, it has been the endeavor of pharmaceutical scientists to provide new forms of aripiprazole, more specifically, a thermodynamically stable form which would have the strengths of the crystalline forms, viz. thermodynamic stability, and those of the amorphous form, viz. enhanced solubility, rapid onset of action and an enhanced bioavailability.Consequently, there is a need for soluble forms of aripiprazole that can be readily formulated for use in various modes of administration, including parenteral and oral administration. Co-crystal complexes of aripiprazole would add a powerful tool in the treatment of central nervous system disorders. The present invention provided co-crystals of aripiprazole and fumaric acid which are stable and are reproducible on an industrial scale.

case

………………WILL BE UPDATED  see end of article

 

Cocrystal Sreening


Cocrystal screening is similar to salt screening in many aspects. The counterions used for salts are usually the same compounds used as the guests, also known as coformers, in cocrystal screens. Rather than the pKa values used for salts, hydrogen-bonding networks and other interactions are used to choose the guesS.  Early cocrystal screens used stoichiometric amounts of API and guest, similar to salt screens. Recent studies have shown that an excess of one component is usually more successful in producing corystals. Ternary phase diagrams have also been useful in understanding cocrystal formation in solvent systems.
Manual and high-throughput cocrystal screens have been reported, and conditions similar to those used for salts are used in these studies as well.Once a cocrystal is found and selected, it is important to perform a second screen to identify the thermodynamically stable form as well as solvated or amorphous forms. As more is learned about the nucleation and crystallization of cocrystals, the number of possible screening techniques will continue to increase to improve the success rate of the screens.

Slurry

Slurries are a common method employed in polymorph screening, and the technique has been extended to cocrystals. Slurry conversion for polymorphs is a dynamic process where the more soluble (less stable) form dissolves and the less soluble (more stable) form precipitates out of the solution. In the case of cocrystals, a critical coformer or API activity is needed in solution; when the concentration is above this activity, the cocrystal will form. When using a slurry method, the solid components are suspended in a solvent, and partial dissolution occurs, resulting in activity values of one for both components; therefore the activity of the slurries will always be greater than the critical coformer activity needed for cocrystal formation, and this will result in precipitation of the cocrystal.
This concept was tested with 16 systems known to form cocrystals. The APIs included caffeine, itraconazole, sulfamethazine, paracetamol, aspirin, flurbiprofen, ibuprofen, carbamazepine, and piroxicam. The coformers used in the study were oxalic acid, maleic acid, malonic acid, glutaric acid, succinic acid, sulfamethoxypyridazine, benzoic acid, 4,4′-dipyridyl, nicotinamide, and saccharin. Known stoichiometries (1:1 and 2:1 API:coformer) were slurried for 12 h to eight days with most cocrystals forming in an hour. Cocrystals were obtained for all 16 compounds. The technique produced known cocrystals for 13 of the systems, new unsolvated cocrystals for two systems, and two new solvated cocrystals for one system. Studies with caffeine,stanolone,and mestanolone have also shown successful cocrystal production using this technique.
The slurry technique can be easily implemented in the laboratory as another way to screen for cocrystals. If mixtures of cocrystals and API or coformer are produced then a different stoichiometry should be tried. Adding diversity to the experiments by varying the stoichiometry and solvents may also produce different polymorphs or solvates of the cocrystals.

Thermal

Thermal methods available for screening cocrystals include binary melting using a hot stage microscope (Kofler technique) and differential scanning calorimetry (DSC). Heating the components above the melting temperature allows interactions to occur in the melt, potentially nucleating cocrystals which then crystallize out of the molten phase. In the case of the Kofler technique, the two compounds are melted adjacent to each other on a glass slide and are mixed by adding a cover slide. In some cases, high-boiling organic solvents can also be used to create a highly concentrated solution which reduces the melting point of the API.Varying the liquid composition and ratio of the API and cocrystal can lead to different forms. The compounds will mix at the melt interface, and a positive reaction is the formation of crystalline material at the melt interface. A negative reaction may result in a eutectic region where no crystallization is observed. The crystals can be characterized using Raman spectroscopy to determine if a cocrystal has formed. For DSC, the two components are placed in a DSC pan and heated past the melt, cooled, and reheated. The endotherms are compared to the pure materials to see if a new transition has occurred that may be due to a cocrystal. Both thermal methods require additional characterization to confirm cocrystal formation.
Screens using the Kofler method have been reported for a number of systems. In the first example, a development candidate with low solubility and bioavailability was screened using 26 guests resulting in five cocrystals (benzoic acid, fumaric acid, gentisic acid, glutaric acid, and salicylic acid). Raman spectroscopy was used for initial characterization to determine cocrystal formation. Cocrystals were scaled up using solution methods with seeds from the thermal experiments. In a second screen using the Kofler method, the guest nicotinamide was paired with a number of drug substances (ibuprofen, fenbufen, flurbiprofen, ketoprofen, paracetamol, piracetam, and salicylic acid). Five cocrystals were found in this study. Seeded solutions were used to grow single crystals of the new phases in order to elucidate the structures and compare the bonding motifs. A rapid DSC cocrystal screen has also been reported using four APIs (caffeine, carbamazepine, sulfamethazine, and theophylline) and five conformers (glutaric acid, nicotinamide, saccharin, salicylic acid, and urea). Eight new cocrystals and eight reported cocrystals were found in this screen. In all cases, an endotherm for the eutectic was found in the DSC scan below the cocrystal melting temperature. Advantages to the DSC screen include the following:  rapid screening,  amenable to automation and high-throughput screening,  small amount of material needed for each experiment, and  no solvent required, making it a “green” technique.
Thermal methods are a way to focus cocrystal experiments or expand the crystallization space by including them with other screening methods. They use a small amount of material, so that a larger number of experiments can be performed when material is limited. These methods are not suitable for thermally labile or volatile systems; therefore, the initial thermal information needs to be collected on the API and guest molecules. For the DSC method, thermal transitions for polymorphic transformations or desolvations may complicate the scan, making the approach unsuitable for some systems.

 Grinding

Neat grinding and solvent drop grinding for cocrystals are the same as described for salts. The advantages of solvent drop grinding over solution crystallization are that dissolution of both cocrystal formers is not required and solvent interactions that might interfere with solute–solute interactions are limited. It has also been shown that this technique can help control cocrystal polymorphs, as described for caffeine:glutaric acid cocrystals.(66)
There are a couple of variations that have been reported for screening studies. An early development compound initially used neat grinding with a mixer ball mill. Twenty-five conformers were used for this stage of the study, and equimolar ratios of the drug (60 mg) and coformer were ground for 20 min. Solids were analyzed, and those that showed a different DSC trace and XRPD pattern were classified as leads. Five cocrystals were found (fumaric acid, salicylic acid, succinic acid, maleic acid, and piperazine). In the second stage of the screen, the leads were produced from solution crystallization or slurry interconversion to get information on scale-up of the materials. In a second study, both neat and solvent drop methods using a mixer mill were investigated to find cocrystal hydrates. Neat milling was performed with hydrated APIs and coformers and the solvent drop grinding used water as a solvent. Theophylline was found to readily form a cocrystal hydrate with citric acid; however, caffeine only produced an anhydrous citric acid cocrystal. On the basis of the results, solvent drop grinding appears to be a more efficient method of screening for cocrystal and API hydrates over neat grinding of hydrated materials.
A slightly different approach was taken with a carbamazepine cocrystal screen that initially used a mortar and pestle to grind the reactants for 4 min.(69) If partial conversion was observed, a solvent drop method using a mixer/mill was employed with eight solvents and eight guests. Cocrystals were produced with all the guests, and it was found that dimethylformamide (DMF) and dimethylsulfoxide (DMSO) produced the most cocrystals. It was also suggested that higher guest solubility would lead to cocrystal formation. A recent repor compared both neat and solvent drop grinding using a novel planetary mixing system which grinds 48 samples simultaneously in 2-mL glass vials. One carbamazepine and three caffeine cocrystals were used as model systems with grinding times of 0.5, 2, and 4 h. All mixtures showed some degree of cocrystallization, and the solvent drop grinding was more effective than the neat grinding. The known forms were found for four systems, and the caffeine:maleic cocrystal samples resulted in three solid forms identified as 1:1 and 2:1 cocrystals, as well as a new unsolvated form.
Grinding experiments have been found to successfully produce cocrystals with solvent drop grinding resulting in more positive results when compared to neat grinding. Different stoichiometries and grinding times are variables that can lead to different cocrystals and possibly different forms. The use of different solvents in solvent drop grinding experiments also increases the crystallization space and can be more focused by using acceptable solvents to produce hydrates and other acceptable solvates when needed for development. Scale-up of cocrystals originally found by grinding are usually performed by using solution crystallization methods and seeds from the grinding studies. Additional work, such as constructing ternary phase diagrams,  may be needed to determine the best solvent(s) and concentrations to readily crystallize the desired form at scale.

Supercritical Fluid

Supercritical fluid crystallization has been used in designing particles and generating polymorphs of APIs. Carbon dioxide is the most common supercritical fluid used for pharmaceutical applications, and it can be used as a solvent or antisolvent, depending on the process used. Reports of cocrystals produced using this method include indomethacin:saccharin cocrystals prepared by supercritical antisolvent (SAS) or supercritical atomization.
A recent study demonstrates how supercritical enhanced atomization (SEA) can be used for cocrystal screening, The SEA process also produces submicrometer particles, which can further enhance bioavailability for poorly soluble drugs. Saccharin was used as the cocrystal former with six APIs (indomethacin, aspirin, carbamazepine, theophylline, caffeine, and sulfamethazine). A 1:1 ratio was used for all APIs along with a 1:2 theophylline:saccharin ratio. The components were dissolved in ethanol which was then mixed with the supercritical fluid before depressurization into the precipitation vessel. Known cocrystals of all the APIs were successfully produced, and a new form of the theophylline:saccharin cocrystal was also found. A narrow size distribution of 0.3–10 μm was observed for all systems, showing that this process can also readily control particle size.
Supercritical fluid crystallization is a more specialized cocrystal screening technique that requires specific equipment, but it can significantly expand the crystallization space into areas that may not be accessible by other more conventional methods. Particle design is an added benefit to this technique where narrow submicrometer particle size ranges could help early formulations. Large-scale production using this method would need to be investigated, or conventional methods using seeding would need to be explored.

Sonochemistry

Sonochemistry involves the use of ultrasound during the cocrystal formation. The components are usually added in stoichiometric amounts to an appropriate solvent to form a slurry which is then sonicated. The solvent is used to mediate the reaction between the components to form a cocrystal, while sonication can help promote nucleation of different forms of the cocrystals.
A report using sonochemistry for a cocrystal screen compared it to the solvent drop grinding approach to investigate the role of the solvent in these experiment.  Theophylline and caffeine were used as the model compounds, and l-malic or l-tartaric acid were used as the guests. The API and guest (about 100 mg total solid) were combined in stoichiometric amounts in a suitable solvent to produce a slurry. Four different solvents were used for each API–coformer pair, and three different concentrations of the solution were prepared to vary the supersaturation of the API and coformer. The reactants were then subjected to an ultrasonic probe at a frequency of 20 kHz and a variable power setting between 0.1 and 100 W. Short pulses over the course of 2–5 min were used to avoid heating the sample. Formation of the cocrystal was reported to be dependent on the saturation level of both the API and coformer. Extremes of high and low supersaturations did not result in cocrystals, and a method to find suitable conditions for cocrystal formation is proposed.
Using sonication in a screen can be implemented with an ultrasonic probe with direct control of the energy input or more simply by using an ultrasonic bath that has less control but may have sufficient energy to effect nucleation compared to no sonication. A number of parameters can be varied, such as solvent, sonication time, sonication power, and supersaturation, in order to make new cocrystals and unique cocrystal forms.

case study

Acetazolamide (ACZ)

Acetazolamide is used mainly in treatment of glaucoma. It is also used as an antiepileptic and anti diuretic agent. It is formulated as tablets, capsules (for extended release) and injection. It is commercially available as Diamox.

Figure 3: The structure of Acetazolamide (Jenniffer I. Arenas-Garcı´a et al.2010)

The above fig 3 shows the structure of acetazolamide. It has two known polymorphic forms (Form A and B). Form A being the more stable form than form B. Acetazolamide has low solubility and permeability. Hence efforts are being made to form and identify new co- crystals forms of the drug (Jenniffer I. Arenas-Garcı´a et al.2010). Co crystals were made by using four different techniques. Co crystals were prepared by using Solvent drop grinding experiments. Out of 20 Co crystal former used 4-Hydroxybenzoic Acid and Nicotinamide were found to form stable co crystals with acetazolamide. Co crystals formed were characterized using XRPD, IR spectroscopy, DSC and TGA techniques.

Figure 4Crystals of acetazolamide (ACZ) and the corresponding co-crystal with 4-hydroxybenzoic acid (ACZ-4HBA) can be distinguished by their different shapes (Jenniffer I. Arenas-Garcı´a et al.2010).

Co crystal phase stability was carried out to check whether the co crystals formed convert to the parent compound ie.ACZ. The co crystals were exposed to water at various physiological pH values. The co crystal formed by ACZ with nicotinamide transformed to ACZ and this was time and pH dependent while co crystal with 4 -hydroxybenzoic acid didn’t transform into ACZ.

 

Figure 5: Molecular conformations of ACZ in the crystal structures of ACZ form A,9a,d AC form B,9c ACZ-4HBA, and ACZNA- H2O. N4-S2-C1-S1 torsion angles are indicated (Jenniffer I. Arenas-Garcı´a et al.2010).

Figure 5 gives the molecular conformation of the available polymorphs of ACZ and the two new co crystals formed. These structural details demonstrate that ACZ possesses two potential sites for the formation of doublebridged homo- and heterosynthons, the carboxamidine (C(N)NH) group on the thiadiazole acetamide fragment and the sulfonamide group(Jenniffer I. Arenas-Garcı´a et al.2010).

Thus the co crystals formed were stable enough at ambient temperature. However this study fails to compare the solubility and permeability of co crystals with ACZ.

Paracetamol

Figure 6 : The Structure of paracetamol (Zimmermann B et al. 2010)

Paracetamol is used as an antipyretic and analgesic. Commercially it is available as tablets, capsules, solutions, suspensions etc. Paracetamol has three known polymorphic form viz. Monoclinic (Form I), Orthorhombic (Form II) and a third instable form III. Efforts were made in characterising form III with use of rapid heating DSC and HPMC (crystal growth modifier) (S. Gaisford. et.al. 2010). Thermal analysis of the polymorphs was carried out using FT-IR spectroscopies (Zimmermann B et al. 2010). Form II is the commercially available form of paracetamol. However form I has a stiffer arrangements in the crystal lattice compared to the orthorhombic metastable form II. Hence form I shows poor compression ability. (Etienne Joiris et.al.1998) Although form II shows better compression ability compared to form I but still form I is preferred as API. This is due to then stability issues related with form II. The stability of the form II varies with alteration in temperature and humidity. Hence, the stability issue prompts the manufacturer to liken form I. Efforts should be made to make form II more stable under ambient temperature and humidity.

Itraconazole

Figure 7: The Structure of Itraconazole (Julius F. Remenar et al.2003)

Itraconazole (Fig 7) is an antimicrobial agent. It is commercially used for treatment of onychomychosis. The main disadvantage for this drug is its solubility. It is a poorly soluble drug. Hence attempts were made to form a co crystal of the drug which will increase the solubility of the drug. Amorphous state of the drug has a greater solubility than the crystalline form but the amorphous form is less stable and degrades quickly in presence of humidity and temperature. Hence in one such attempt a co crystal of itraconazole was prepared using 1,4-dicarboxylic acids (Julius F. Remenar et al.2003). A trimeric co crystal was prepared with itraconazole atoms at the two ends of the dicarboxylic acid (Succinic acid).

Figure 8: Dissolution profile of itraconazole

From the fig 8 we can conclude that the co crystal with malic acid matches the solubility that of the amorphous itraconazole (Julius F. Remenar et al.2003). Thus this study suggests that it is possible to have a form which matches the bioavailability of the amorphous form but has the physical and chemical stability of the crystalline form.

Fluoxetine

Figure 9: Co crystal of Fluoxetine – Succinic acid (Scott L. Childs et al. 2004)

Fluoxetine is a selective serotonin reuptake inhibitor. It is indicated for acute and maintenance treatment of Major Depressive Disorder (MDD), Obsessive Compulsive Disorder (OCD), and Panic Disorder. (Drugs@FDA). It is commercially marketed as tablets, capsules (for sustained release) and solution (discontinued). Crystalline form of the drug shows poor solubility. Hence efforts were made to develop a co crystal which will have increased solubility compared to the crystalline form. Co crystals were prepared using 1,4-dicarboxylic acids (Scott L. Childs et al. 2004). The above figure 9 shows the co crystal formation between fluoxetine and succinic acid. Co crystallization takes place due to hydrogen bond interactions. The formation of co crystal was confirmed with single crystal structure X-Ray diffraction and IR spectroscopy.

Figure 10: Dissolution profile of the co crystals (Scott L. Childs et al. 2004)

From the fig 10 we can see that distinctive dissolution profiles can be achieved through co crystallization. Hence these forms of API’s can be used to make alternate formulations.

 

 

case study

Efficient Purification of an Active Pharmaceutical Ingredient via Cocrystallization: From Thermodynamics to Scale-Up

Chemical Development/Physical Quality, Analytical Sciences/Solid State, Sanofi R&D, LGCR, 9 quai Jules Guesde, 94403 Vitry sur Seine cedex, France
Org. Process Res. Dev., 2013, 17 (3), pp 505–511
FigureStructure of SAR1.
Abstract Image

Cocrystallization as a purification step was the only way to isolate an active pharmaceutical ingredient with acceptable chemical and physical specifications. The process design controlling chemical quality and polymorphism issues is described, from the thermodynamics of cocrystal formation and cleavage, to microscale data acquisition, to laboratory scale-up and transfer to the pilot plant.

 Figure

Figure 14. Raman in situ monitoring (red and blue curves, peaks specific to API, green curve, specific to cocrystal).

Conclusion


An efficient cocrystallization was developed to purify an API resistant to classical purification techniques. Mastery of phase diagrams involved in cocrystallization allowed us to quickly choose first the best coformer that was compatible with the chlorobenzene feedstock of API and then to recover a purified API within specifications for residual solvent and crystalline form. Processes developed at laboratory scale on a pure API were transferred without any difficulties to the representative crude API. Selected cocrystallization and cleavage processes were improved to fit with pilot plant constraints and scaled to deliver 10 kg batches. The process developed at laboratory scale was successfully transferred to the pilot plant. At pilot-plant scale starting with an API assaying 65%, the benzoic cocrystal step improved purity to 99%. After cocrystal cleavage purity remained the same or was slightly increased. The overall yield for the two steps was 54%. The final product was within the ICH specifications for residual solvents content and for polymorphic form. As the majority of impurities were of unknown structure, it is difficult to explain why cocrystal formation is so selective for the API.
The cocrystal screening has been subsequently extended beyond the already known five cocrystals, and 24 new hits have been found. A crystal structure was solved from single-crystal diffraction data. Contrary to expectations, there is only one hydrogen bond, and not two, between an acid hydroxyl and a urea carbonyl. A perspective to further understand the cocrystallization phenomenon in this system is to test purification efficacy of these new cocrystal hits so as to reveal relationships between the purity and specific hydrogen-bond patterns within cocrystals.

Experimental Section


On a micro scale, the acquisition of basic data including solubility curves, metastable zone widths, shapes of ternary phase diagrams, and confirmation choice of coformers, as well as the identification of the solvents and optimal concentrations to return from cocrystal to API were done with the Crystal16 system (Avantium, Amsterdam, Netherlands). This system contains 4 × 4 reactor blocks of 1.5 mL HPLC vials agitated by magnetic fleas. Each block is independently electrically heated and cooled by a combination of Peltier elements and a cryostat. Each vial contains a turbidity sensor to detect dissolution and nucleation points.
Cocrystals were screened using the solvent drop grinding method.(10) The method consists of milling in expected molar ratios the API and the cocrystallizing agent. Addition of a few drops of solvent increases kinetics. Grinding was performed on a Retsch MM200 mill for 20 min at 30 Hz with one 4 mm ball in the milling chamber. The API quantities were between 50 and 200 mg and solvent about 30 μL. Possible hits were checked by X-ray powder diffraction (XRPD).
At a laboratory scale, crystallization experiments were carried out in a 300-mL jacketed reactor. The temperature was regulated by a Huber Unistat Tango unit (VWR, Fontenay-sous-bois, France). The reactor was equipped with a four-pitch blade turbine, Pt-100 probes, and a turbidity probe (Anglia, Cambridgeshire, UK) connected to a transmitter Trb8300 (Mettler Toledo, Paris, France). The software Labworldsoft (IKA Werke GmbH & Co. Staufen, Germany) was used to acquire mass and jacket temperatures, stirring speed, and turbidity signals.
The crystallization processes at a 10–15 kg scale in the pilot plant were carried out in a 160 L crystallizer fitted with a retreat curve agitator.
Differential scanning calorimetry (DSC) was performed with a Q200 system (TA Instruments, New Castle, DE) using nonhermetically sealed 20 μL aluminum sample-pans. Sample masses for analysis were 3–5 mg with a heating rate of 10 K min–1.
Thermogravimetric analysis (TGA) was carried out with a Q5000 system (TA Instruments, New Castle, DE). Sample masses were 5–10 mg, and heating rate was 10 K min–1.
XRPD patterns were obtained on a Bruker D-8 X-ray diffractometer equipped with θ/θ-goniometer (Bruker AXS, Karlsruhe, Germany) using Cu Kα radiation (tube voltage 40 kV, tube current 40 mA) from 2 to 40° 2θ at a rate of 0.006° 2θ s–1. The diffractometer was fitted with variable entrance slit and a Lynxeye detector.
X-ray single-crystal diffraction (XRSCD) was carried out with a Smart Apex three circle single crystal diffractometer (Bruker AXS, Karlsruhe, Germany) using Mo Kα radiation.

 

 

 

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