PHARMACEUTICAL CO-CRYSTALS - AN APPROACH TO INCREASE SOLUBILITY AND BIOAVAILABILITY

Venugopalaiah. P, D.Sravanthi, M.Gobinath, B.Kumar, R.Dinesh

1Ratnam Institute of Pharmacy, Pidathapolur, Nellore-524346, Andhra Pradesh, India.2Swathi College of Pharmacy, Venkatachalam, Nellore-524323, Andhra Pradesh, India.

ABSTRACT

In order to formulate a successful dosage form, researchers should rely on various physicochemical properties of active pharmaceutical ingredient (API). Pharmaceutical industry is striving hard on various limitations encountered by API like stability, solubility, bioavailability and mechanical properties. Among various solid state forms like polymorphs, solvates, hydrates and amorphous solids, crystals and crystalline solids gain much importance in pharmaceutical industry due to their higher stability and reproducibility. Taking this into the account more research was done on crystals and crystalline properties of API, which leads to inventing a new method called co-crystallization with improved properties of solubility and bioavailability even on high temperatures and high relative humidity. Co-crystallization technique provides effective means to discover alternate solid dosage forms in various complex organic molecules. Hence this review explains about the advantages and disadvantages, properties and methods for the preparation of co-crystals, characterization techniques, recent advancements and various marketed preparations of pharmaceutical co-crystal.

KEY WORDS:

Co-crystals, Supra molecular complexes, Solubility, Bioavailability, X-ray diffraction etc.

INTRODUCTION

A co-crystal is a crystalline solid compose with two or more molecules at ambient temperatures, that interact via charge, neutral, non- covalent bonds. Crystal lattice of co-crystals may consist of solvent/water molecules. Co-crystals may enhance the pharmaceutical properties by modifying the chemical stability, moisture uptake, solubility and bioavailability. Co-crystals can be formed by various interactions like hydrogen bonding, pi-stacking and vanderwals forces. First reported co-crystal was studied By Friedrich Wohler in 1844 & was Quinhydrone (co-crystal of Quinone & Hydroquinone). Pharmaceutical co-crystals are the stoichiometric ratios of a pharmaceutical agent and co-crystal former (CCF) where both are solids at ambient temperature[1]. Co-crystals may be discovered by coincidence or by screening techniques. A pharmaceutical co crystal can be designed by crystal engineering with the intention to improve the solid-state properties of an API without affecting its intrinsic structure.[2] Co-crystals can be considered as molecular complexes which differ from solid solutions or mixed crystals. Co-crystals are divided into co-crystal anhydrates and co-crystal hydrates.[3]

Fig-3: Various types of solids

Salts can be differentiated from co-crystals in that, the former mainly improve solubility and stability of a compound, while the later is an alternative to salt when salts do not have solid properties due to the absence of ionisable salts in API. Structural properties of a co-crystal is base on structure of CCF. Examples of CCF include ascorbic acid, gallic acid, nicotinamide, citric acid , aglutamic acid, histidine, urea, saccharine, glycine, tyrosine, valine etc. [4]

PHYSICO-CHEMICAL PROPERTIES OF CO-CRYSTALS

Melting point

Melting point is the temperature at which the solid phase is at equilibrium with the liquid phase. Melting point was found to be an important physical property where many physico-chemical properties like processability, solubility and stability of drug depends on it. Eg: Co-crystals of pyrazine with n-alkyl carboxylic acids exhibit some regularity on their melting points.For those acids longer than C7 (heptanoic acid and longer acids), the corresponding co-crystal show an alternation in their melting point which is opposite to that in the n-alkyl carboxylic acids themselves. The melting points of the odd co-crystals are systematically higher than those of the evens since they have systematically higher packing efficiency at the methyl-group interface between layers in the structures.This example shows that melting point of co-crystals mainly depends on co-crystal formers and can be changed by co-crystallization. However, higher melting point does not represent higher thermal stability. [5]

HygroscopicityStability of a solid drug in the presence of atmospheric moisture can be explained clearly by hygroscopicity. Co-crystals generally exhibits less hygroscopicity than a crystal.

Eg:In the case of co-crystal of an active pharmaceutical ingredient (API) with phosphoric acid, compared with the API itself, the co-crystal has improved chemical and physical stability to

APISalt

humidity. [6] A systematic study on the co-crystals of caffeine with several carboxylic acids showed that they generally have less hygroscopicity than caffeine. The cocrystal with oxalic acid even exhibits complete stability to humidity over a period of several weeks.[7]

Mechanical propertiesIn order to design a dosage form mechanical properties of API plays a prominent role. Mechanical properties of API helps in formulation and processing of drug products. The crystalline structural properties influence these mechanical properties. Eg: Slip planes in the 1:1 caffeine-methyl gallate co-crystal have been correlated with improved tabletability. The caffeine co-crystal produced higher tensile strength than pure caffeine and pure methyl gallate across all compaction pressures (~40-400 MPa). [8]

StabilityCo-crystals were found to be more stable when compared to crystals and other solids, which shows less polymeric transformations due to its higher complexity thus improving the stability of a co-crystal. Eg: Temozolamide (TMZ) is obtained as a white powder but turns pink and then brown, which is indicative of chemical degradation. Pharmaceutical co-crystals of TMZ were engineered with safe conformers such as oxalic acid, succinic acid, salicylic acid, d,l-malic acid, and d,l-tartaric acid, to stabilize the drug as a cocrystal. The half-life (t1/2) of TMZ-oxalic and TMZ-salicylic acid measured by UV/Vis spectroscopy in pH 7 buffer is two times longer than that of TMZ (3.5 h and 3.6 h vs. 1.7 h); TMZ-succinic acid, TMZ-tartaric acid, and TMZ-malic acid also exhibited a longer half-life (2.3, 2.5, and 2.8 h, respectively). [9]

SolubilityCo-crystal solubility is dependent on solution composition and pH. Co-crystal solubility can be calculated by using the following equation.

[R]T = Total drug concentration at equilibrium, Ksp = Solubility product of co crystal, Ka = acid ionization constant, [A]T = Total co-former concentration, [H+] = Hydrogen ion concentration.

Co-crystal solubility is predicted to increase with pH and decreases as the co-former concentration solution increases. [10]

Intrinsic dissolutionIntrinsic dissolution measures the rate of dissolution of a pure drug substance from a constant surface area, which is independent of formulation effects and measures the intrinsic properties of the drug as a function of dissolution media, e.g. pH, ionic strength and counter-ions. Most of the APIs studied for cocrystallisation are classified as BCS (Biopharmaceutics Classification System) class II drugs, which have high permeability and low solubility. Thus, intrinsic dissolution rate is a good indicator for in vivo performance of APIs.Eg: A low solubility API, 2-[4-(4-chloro-2 fluorophenoxy) phenyl] pyrimidine-4-carboxamide, was cocrystallised with glutaric acid to achieve 18 times higher intrinsic dissolution rate.[11]

BioavailabilityBioavailability is a measurement of the extent to which a drug reaches the systemic circulation. This is the main physico chemical property for a pharmaceutical co-crystal.Eg: The co-crystal of glutaric acid and 2-[4-(4-chloro- 2 fluorphenoxy) phenyl]-pyrimidine-4-carboxamide (PPPA) was used to demonstrate an improvement in the oral bioavailability of the API in dogs. Single dose dog exposure studies confirmed that the co crystal increased plasma AUC (area under the plasma concentration time curve) values by three times at two different dose levels, these in-vivo studies were in agreement with aqueous rotating disk intrinsic dissolution results that indicated significant improvement for the cocrystal (~18-fold increase) over the pure drug at 370c. [12] Carbamazepine-saccharin (1:1) cocrystal has exhibited higher average cocrystal Cmax and AUC values relative to the marketed form III of carbamazepine in beagle dogs. [13]

DESIGNING A CO-CRYSTAL

In designing co-crystal intermolecular interactions that direct molecular assembly is considered as a key point in co-crystal design. One of the most useful interactions would be hydrogen bonds, due to their inherently robust and directional nature.[14] A good hydrogen bond acceptor or a hydrogen bond donor can be used to form hydrogen bonds. A system which has a tendency to maximize electrostatic interaction results in that the best hydrogen bond donor ends to interact with the best hydrogen bond acceptor in a given crystal structure.[15] This phenomenon is concluded as hydrogen-bond rules which can be used as a guide line for co-crystal design.

METHODS OF CO-CRYSTALLIZATION

Co-crystals can be produced by various methods like Slow-solvent evaporation, Slow Cooling, melt crystallization, Sublimation, Mechanochemistry (Neat grinding/Dry grinding), Liquid assisted grinding (Kneading/solvent drop grinding), Sonochemistry, or solution-mediated phase transformation (SMPT), Solution crystallization, Twin screw extrusion, Matrix assisted co-crystallization by hot melt extrusion, Microwave irradiation method. [16,17]

Slow solvent evaporation

This is one of the simplest methods and is generally the first attempted. This method is suitable for compounds that are stable to air and moisture at room temperature. This method involves the slow evaporation of the solvent from the solution containing the compound until saturation is reached and crystals begin to form. It works best when there is enough material to make 1–3 mL of saturated or near-saturated solution. A saturated solution is prepared and transferred to a vial or crystallization dish. The dish is covered with a piece of pierced aluminium foil or a pierced lid is placed on the vial and the sample is left in a safe place while the solvent evaporates. If using a vial, it can be placed at an angle in a beaker (Fig. 2). This will encourage the crystals to grow on the side of the vial as more solvent is in contact with the side and the angle prevents newly-

formed crystals falling straight to the bottom of the vial. Due to the narrowness of the vial, crystals on the side are easier to remove from the vial without damaging them. The beaker will also protect the vial from accidently being knocked over. A disposable needle can be left in the lid if required to stabilize the vial at the right angle. [18]

Figure 2. Slow evaporation technique using a vial.

Slow Cooling

This is simple and successful technique. Most substances are more soluble at higher temperatures than lower temperatures and almost any solvent can be used. The technique involves cooling a saturated solution. As the temperature drops, the solvent's ability to dissolve the solute decreases and excess solute precipitates out. If the rate of cooling is slow enough, crystals should form. When crystallization is to be ensured from hot solvent, it is important to cool the sample in a stepwise manner. Heat the solution, cool the solution to room temperature. After this keep the solution in fridge first followed to freezer. Ideal solvents for this technique are those in which your compound displays high solubility at high temperature and low solubility at low temperature. Unsuitable solvents are water and benzene if the sample is going to be placed in the freezer.

A variation on this method uses a Dewar flask and a water bath shown in Fig. 3. This set-up is designed to allow the solvent to cool as slowly as possible, so that it will take several days or weeks for crystals to form. It is suitable for solvents with boiling points in the range 30–90°C and the compound should be thermally stable. [18]

Figure 3. Slow cooling of a sample with a Dewar flask.

Suspension Melt Crystallization

The suspension melt crystallization process operates with a simple vessel type crystallizer shown in figure 4,5 including the growth volume with the scraped surface area. The large number of crystals provide a massive growth surface in a relatively small volume. Since this large surface absorbs the under-cooling of the solution, the resulting overall growth rate is extremely low. This slow, near ideal, growth allows the formation of pure crystals in a single crystallization step. The pure crystals must be completely separated from the impurities remaining in the mother liquor. The separation is accomplished within the unique wash column.

Fig 4: GEA Messo PT wash column

Fig 5: GEA Messo PT Crystallizer

A reciprocating piston/filter draws a charge of crystal slurry into the wash column and compresses this charge into a compact bed of crystals while allowing the mother liquor to leave through the filter. The scraper starts and the piston/filter continues to force the existing crystal bed through the column as the scraper disintegrates the bed at the opposite end of the column. The pure melted product is forced counter-current to the crystal bed flow. This counter-current wash flow effectively removes the impurities remaining around the crystals and returns the wash liquid as pure product crystals. The washed crystal bed is disintegrated by a rotating scraper. [19]

Sublimation

The sample may be heated in order to increase its vapour pressure. The application of a vacuum to the apparatus encourages vaporization and enhances the sublimation. Selectively cooling part of the apparatus increases the efficiency of the condensation process. Using an entraining gas can improve the mass transport in the system and thereby increase the overall efficiency of the sublimation process.

The simplest form of sublimation apparatus consists of a beaker or porcelain dish on top of which is placed an upturned watch-glass. Sample to be sublimed is taken in a beaker and the sample is sublimed on lower surface of the watch glass shown in figure 6. A perforated filter paper is commonly placed between the beaker and the watch-glass to prevent sublimate falling back into the sample. Sublimation can also be done by using an upturned funnel instead of a watch-glass as the condensing surface and an appropriately placed sealing ring improves the performance, the experimental set up is shown in figure 7. [20-23]

Fig 6: Sublimation Crystallization. S, sample; P, sublimate; FP, perforated filter paper.

Fig 7: Apparatus for simple sublimation at atmospheric pressures

Mechano Chemistry

Neat Grinding/Dry Grinding

Neat grinding involves the mixing of stoichiometric co-crystal components together and grinding them either manually, using a mortar and pestle, or mechanically, using a ball mill or a vibratory mill. This method requires one or both reactants exhibiting significant vapour pressures in the solid state.

Liquid assisted grinding

Solvent drop grinding involves the grinding of two materials together and a small quantity of solvent. [24] The solvent here is used as a catalytic role, to enable the formation of co-crystals not obtained by neat grinding. And the solvent molecules will not exist in the final product. Some

co-crystals could be prepared by both neat grinding and solvent drop grinding, such as the co-crystals of some carboxylic acid with trimethoprim and pyrimethamine. [25,26]

Sonochemistry:

Sonochemistry is the recent advancement in the preparation of co-crystals. Effect of ultrasound on crystallization of various compounds increased in past decade. This involves generation of bubbles during the rarefaction cycle of the waves. Due to the collapse of these cavities pressure of several thousand atmospheres is generated which is used to control the nucleation. Ultrasound assisted crystallization process is called as sonocrystallization in which the nuclei are produced due to cavitation and ultrasound contols the growth of crystals. During sonocrystallization ultrasound reduces the particle agglomeration and increases the supersaturation resulting in more stable, definite size particles. [27]

Twin Screw Extrusion

Extrusion has become apparent as a feasible platform for the development of pharmaceutical co-crystals. Twin screw extruders (TSEs) has been proven to be a consistent and repeatable way to make high-quality products.

TSE shown in figure 9 mainly depends on screws and has an infinite number of screw variations possible. Basic type of screw elements include flighted elements, mixing elements, and zoning elements. Flighted elements forward material past barrel ports, through mixers and out of the extruder to pressurize the die. Zoning elements isolate two unit operations. Screw designs can be made shear-intensive or passive, based upon the elements used in the design. Mixing elements can be dispersive and/or distributive, or a combination thereof. The kneader is the most prevalent mixing element used in a TSE. Narrower kneaders are more distributive in nature that force high melt division rates with significantly less extensional and planar shear effects. Distributive mixing elements can be particularly useful for mixing heat and shear-sensitive materials. Kneading elements can be arranged with a forward pitch (less aggressive), neutral, or reverse pitch (most aggressive).

Fig 8: Twin screw extruder with feeders for processing pharmaceuticals

In a co-rotating, intermeshing TSE, “self-wiping” screws are seen and the surface velocities of the screws in the intermesh region are in opposing directions, which results in the materials being “wiped” and forced to follow a figure 8 pattern down the length of the screws. Mechanism is showed in figure 9. [28]

Fig 9: Co-rotating, intermeshing screws—“self-wiping”

Matrix assisted co-crystallization using melt extrusion

Matrix-Assisted Cocrystallization (MAC) is introduced herein as a novel method of manufacturing pharmaceutical co-crystals, by extruding a drug and coformer in the presence of a functional matrix material made liquid by the temperature of the extruder. MAC is a solvent-free, scalable, and potentially continuous process that minimizes degradation of the drug and coformer by reducing thermal and mechanical stresses during production compared to other solid-state co-crystallization methods. [29]

Fig 10:Hot Melt Extrusion Process

Microwave irradiation method

Microwaves are electromagnetic waves which contains the components of electric and magnetic fields.It is well known that the interaction of dielectric materials, liquids or solids, with microwaves leads dielectric heating. Electric dipoles present in such materials respond to the applied electric field. In liquids, this constant reorientation leads to the friction between molecules, which subsequently generates heat [30]. Microwave irradiation as a heating method has found a number of applications in chemistry. The microwave synthesis, which is generally quite fast, simple and efficient in energy, has been developed and is widely used in various fields such as molecular sieve preparation, radiopharmaceuticals, the preparation of inorganic complexes and oxide, organic reactions, plasma chemistry, analytical chemistry and catalysis [31].

Eg: Using the microwave irradiation method (Ic), co-crystals were obtained for propiconazole with 2,2'-dihydroxy-l ,l '-dinaphthalene, D-ribose, maleic acid and oxalic acid. [32]

CHARECTERIZATION OF CO-CRYSTALS

Single crystal X-ray Diffraction:SXRD is a basic characterization technique for determination of the solid state structure of co crystals at an atomic level. But single pharmaceutical co-crystal which is qualified for SXRD testing cannot always be produced. Therefore, PXRD are utilized more frequently to verify the formation of co crystals.

Fig 11: Single crystal X-Ray Diffractometer

Powder X-ray DiffractionPowder X-Ray Diffractometer is a compact advanced instrument shown in figure-11 that has various salient features and new accessories like variable temperature assembly and humidity chamber etc. When X-ray falls over a crystal, it diffracts in a pattern characteristic to its structure. In powder X-ray diffraction, the diffraction pattern is obtained from a powder of the material, rather than an individual crystal. Powder diffraction is often easier and more convenient than single crystal diffraction as it does not require individual crystals. A diffraction pattern plots intensity against the angle of the detector, 2θ and the graph obtained is called as diffractogram which is shown in figure 13. [33-35]

Fig 12: Powder X-Ray Diffractometer

Fig 13: XRD diffractogram of the graphite nanoplatelet sample

Raman Spectroscopy:Raman is a vibrational spectroscopy that provides rich information about the identity of molecular species. [36] In Raman spectroscopy a laser source is needed to excite the target species.  Hollow cathode ion laser is used that produces light at 224 and 248 nm.  Ultraviolet excitation has been particularly successful in obtaining spectra of organic molecules.  A filter collects the Raman scattered light (Stokes) and filters out the Raleigh and Anti Stokes light. A diffraction grating bends the Raman shifted light according to wavelength. A detector records the signal and passes the signal to a computer for decoding. [37]

Fig 14: Pictorial representation of Raman spectroscopy

Scanning Electron Microscope:

Fig 15: Scanning Electron Microscope

The scanning electron microscope (SEM) uses a focused beam of high-energy electrons to generate a variety of signals at the surface of solid specimens. The signals that derive from electron-sample interactions reveal information about the sample including external morphology (texture), chemical composition, and crystalline structure and orientation of materials making up the sample. The SEM is also capable of performing analyses of selected point locations on the sample; this approach is especially useful in qualitatively or semi-quantitatively determining chemical compositions, crystalline structure, and crystal orientations.[38]

Terahertz time-domain-spectroscopy (THz-TDS):

Terahertz time-domain-spectroscopy (THz-TDS) has emerged as a versatile spectroscopic technique, and an alternative to powder X-ray diffraction in the characterization of molecular crystals. It has been demonstrated that terahertz spectroscopy has the ability to distinguish between chiral and racemic hydrogen bonded co-crystals that are similar in molecular and supramolecular structure. The investigation of the co-crystal of theophylline with chiral and racemic forms of coformers using PXRD and Raman spectroscopy suggested that THz-TDS is comparable in sensitivity to diffraction methods and more sensitive than Raman to changes in co-crystal architectures. [39]

RECENT ADVANCEMENTS IN CO-CRYSTALS

Many improvements have been seen in recent years in the processing of co-crystals. Here we focused on some recent advancements in co-crystals based on Biopharmaceutical Classification System (BCS). Many researches are done on BCS class II drugs in order to improve the solubility of the compound.

BCS CLASS-I

The formation of a co-crystal involving pyrazinamide, one of the first-line drugs recommended by the World Health Organization for tuberculosis treatment, and diflunisal, a nonsteroidal anti-inflammatory substance, is investigated. From a combination drug perspective, this is an interesting co-crystal because of the known side effects of pyrazinamide therapy. A 1:1 co-crystal is successfully synthesized by three different methods like thermal activation, neat grinding and solvent assisted grinding. [40]

BCS CLASS-II

The Prulifloxacin (PF)-Nicotinamide (NCT) cocrystals was prepared by employing slow evaporation and solution crystallization methodology from acetone as a solvent. The results from Powder X-ray diffraction, DSC, IR, Raman spectroscopic analysis revealed the formation of co-crystal of prulifloxacin and nicotinamide. The PF-NCT cocrystal is moderately hygroscopic and exhibit enhanced solubility than the pure drug. This study confirms co-crystallization offers a valuable way to improve the physicochemical properties of the API. [41]

Piroxicam was chosen as a model compound to explore co-crystal formation in this research because it is a Biopharmaceutics Classification System (BCS) Class II compound. A total of seven slow evaporation experiments with piroxicam and five carboxylic acid coformers in either 1:1 or 2:1 piroxicam/acid stoichiometric ratios were performed. No chemical degradation was observed. A stability study of piroxicam in all the solvent combinations proved piroxicam to be stable at room temperature for at least 42 days. [42]

A 1:1 danazol:vanillin cocrystal, was formulated as neat aqueous suspension. Danazol:vanillin cocrystal had a modest in vivo improvement of 1.7 times higher area under the curve compared to the poorly soluble crystal form of danazol dosed under identical conditions, but the formulated aqueous suspension containing 1% vitamin E-TPGS (TPGS) and 2% Klucel LF Pharm hydroxypropylcellulose improved the bioavailability of the co-crystal by over 10 times compared to the poorly soluble danazol polymorph. In vitro powder dissolution data obtained under non-sink biorelevant conditions correlate with in vivo data in rats following 20 mg/kg doses of

danazol. In the case of the danazol:vanillin cocrystal, using a combination of cocrystal, solubilizer, and precipitation inhibitor in a designed supersaturating drug delivery system resulted in a dramatic improvement in the bioavailability. [43]

Considerable improvement in the dissolution rate of fenofibrate from optimized co-crystal formulation was due to an increased solubility that is attributed to the super saturation from the fine co-crystals is faster because of large specific surface area of small particles and prevention of phase transformation to pure fenofibrate. In vitro dissolution study showed that the formation of co-crystals improves the dissolution rate of fenofibrate. Nicotinamide forms the co-crystals with fenofibrate, theoretically and practically. [44]

Nitrofurantoin (NTF) co-crystals were prepared to increase its solubility. Screening for cocrystals of NTF using 47 coformers was performed by high-throughput (HT) screening using liquid assisted grinding (LAG) methods. Raman spectroscopy and powder X-ray diffraction (PXRD) were used as the primary analytical tools to identify the new crystalline solid forms. The solution stability of the scaled-up cocrystals in water was tested by slurrying the cocrystals at 25 °C for one week. NTF forms cocrystals with a 1 : 1 stoichiometric ratio with urea, 4-hydroxybenzoic acid, nicotinamide, citric acid, L-proline and vanillic acid. In addition, NTF forms a 1 : 2 cocrystal with vanillin. All but one of the NTF cocrystals transformed (dissociated) in water, resulting in NTF hydrate crystalline material or NTF hydrate plus the coformer, which indicates that the transforming co-crystals have a higher solubility than the NTF hydrate under these conditions. [45]

BCS CLASS-III

This invention provides new crystalline forms of dapagliflozin, namely a dapagliflozin lactose co-crystal and a dapagliflozin asparagineco-crystal, pharmaceutical compositions comprising these forms, methods for their preparation and uses thereof for treating type 2 diabetes. The new co-crystal forms of the present invention have adequate stability characteristics enabling their incorporation into a variety of different formulations particularly suitable for pharmaceutical utility. [46]

BCS CLASS-IV

Hydrochlorothiazide (HCT) is a diuretic and a BCS class IV drug with low solubility and low permeability, exhibiting poor oral absorption. Multicomponent crystals of HCT with nicotinic acid (NIC), nicotinamide (NCT), 4-aminobenzoic acid (PABA), succinamide (SAM), and resorcinol (RES) were prepared using liquid-assisted grinding, and their solubilities in pH 7.4 buffer were evaluated. Diffusion and membrane permeability were studied using a Franz diffusion cell. Except for the SAM and NIC co-crystals, all other binary systems exhibited improved solubility. All of the cocrystals showed improved diffusion/membrane permeability compared to that of HCT with the exception of the SAM cocrystal. [47]

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