Monday, May 21, 2012

PERFORMANCE AND STABILITY OF CO-CRYSTAL


BIOPHARMACEUTICAL PERFORMANCE AND STABILITY OF CO-CRYSTAL


INTRODUCTION

As the Biopharmaceutics Classification System (BCS) class-II drugs exhibits poor aqueous solubility and high permeability, formulation development of this class drugs remains a challenge. This class of drugs is currently estimated to account for about 30% of both commercial and developmental drugs. Numerous approaches to resolve this issue of poor aqueous solubility and bioavailability are well reported in scientific literature. These strategies include micronization,[1-3]  use of salt forms,[4] co-solvent approach,[5] micellar solubilization, [6] and complexation with cyclodextrins.[6] Crystal engineering approaches, which can potentially be applied to a wide range of crystalline materials, offer an alternative and potentially fruitful method for improving the solubility, dissolution rate and subsequent bioavailability of poorly soluble drugs. The challenges of low aqueous solubility provide an ideal situation for the application of crystal engineering techniques for improving bioavailability.[7]
Solubilization technologies such as micellar systems are reliant on the acceptable solubility and compatibility of therapeutic molecules in a limited range of pharmaceutically acceptable excipients, while the increasing number of weakly ionizable and neutral molecules entering development phase constrains the opportunities for salt formation as a method for improving dissolution rate. Furthermore, it was reported that only increase in dissolution rate is insufficient to provide adequate enhancement of bioavailability.[9] So, approaches which can improve the aqueous solubility of the drug would be of great help for delivering BCS class-II drugs.
Crystal engineering has evolved in such a manner that it is now synonymous with the paradigm of supra-molecular synthesis, that is, it invokes self-assembly of existing molecules to generate a wide range of new solid forms without the need to break or form covalent bonds. Co-crystals incorporate pharmaceutically acceptable guest molecules into a crystal lattice along with the active pharmaceutical ingredient, changing the physical properties of the solid. Pharmaceutical co-crystals consist of two or more components that are solid at room temperature. Although this definition may be debatable, it provides sufficient differentiation from solvates or other two-component systems. This characterization is therefore well-suited for describing new, possible solid forms for pharmaceutical applications.[10]

Techniques Used in the Formation of Co-crystals
Synthesis of a co-crystal from solution might be thought of as counterintuitive since crystallization is such an efficient and effective method of purification and as such it is used widely in the pharmaceutical industry for isolation of single component crystals. However, if different molecules with complementary functional groups result in hydrogen bonds that are energetically more favorable than those between like molecules of either component, then co-crystals are likely to be thermodynamically (although not necessarily kinetically) favored. Co-crystals involving these supra molecular synthons are usually synthesized by slow evaporation from a solution that contains stoichiometric amounts of the components (co-crystal formers); however, sublimation, growth from the melt, slurries, and grinding two solid co-crystal formers in a ball mill are also suitable methodologies.[12, 13] More often than not, the phase that is obtained is independent of the synthetic methodology. The recently reported technique of solvent-drop grinding, addition of a small amount of suitable solvent to the ground mixture to accelerate co-crystallization appears to be a particularly promising preparation method. Solvent drop grinding avoids excessive use of crystallization solvent and hence it can be regarded as a “green process. Moisture sorptions by hygroscopic materials can also lead to deliquescence, which may further lead to co-crystal nucleation and growth because co-crystal solubility and thermodynamic stability are dependent on solution chemistry.[14]

Biopharmaceutical performance

Solubility: Solubility of the active pharmaceutical ingredient is one of the important factors taken into consideration while developing its dosage form. Class-II drugs of BCS need improvement of their solubility so as to optimize their bioavailability. Co-crystals can be made for ionizable as well as nonionizable drugs. For ionizable drugs, numbers of suitable co-crystal formers are available which implies that there is great potential to form highly soluble and stable pharmaceutical co-crystals.[15] Co-crystal solubility is proven to be dependent on the concentration of co-former in solution. The dissociation of co-crystal in solution is described by the solubility product (Ksp), which is defined as a product of drug and ligand solution concentrations.[16] Co-crystal solubility is considered as a function of the solubility product such that high Ksp values equate to high co-crystal solubility. The co-crystal solubility can be best studied by understanding following thermodynamic calculations.
Co-crystal solubility (Scc) and solubility product (Ksp):
Consider a co-crystal Aα Bβ , where A is drug and B is co-former, then the solubility of cocrystal and equilibrium constant are given by:

                                                        Aα Bβ = αA(soln) + βB(soln)                                                    (1)
           
                                                                                       K  =  ααA(soln)  αβB(soln)
                                                                                                   _____________________
                                                                        αAα Bβ (S)


Keeping solid co-crystal activity equal unity and assuming the activity coefficients of A and B equal unity for low solute levels, equation 1 can be rearranged as
                                                                                                          
                                                                     Ksp = [A]α [B]β                                                           (2) 

where Ksp = solubility product of the co-crystal.

Co-crystal solubility (Scc) and the phase solubility diagram (PSD):
Phase solubility diagrams are used to represent the solubility and solution stability of co-crystals. The phase solubility diagram in Figure-1 illustrates two cases, where case-1 represents stable co-crystal (low solubility and Ksp) and case-2 represents metastable co-crystal (high solubility and Ksp) with respect to the pure drug form in a given solvent.
The curves in figure represent co-crystal solubility product behavior with the drug concentration as a function of ligand given by [drug]α = / [ligand]β from equation-2. The horizontal line represents drug solubility which is assumed to be much lower than the ligand solubility. A dashed line represents stoichiometric solution concentrations of co-crystal in pure solvent and its intersection with the co-crystal solubility curves (marked by circles) indicates the maximum drug concentration associated with the co-crystal solubility. For a metastable co-crystal (case-2), the drug concentration associated with the co-crystal solubility is greater than the solubility of the stable drug form (horizontal line). As a metastable co-crystal dissolves, the drug released into solution can crystallize because of super saturation. This super saturation is a necessary, but not sufficient condition for crystallization. For both congruently and incongruently saturating co-crystals a eutectic point, indicated by X marks in figure, is the point where both solid drug and co-crystal are in equilibrium with a solution containing drug and ligand. Together the drug and ligand solution concentrations at the invariant point are referred to as the transition concentration (Ctr).[17, 18]
Co-crystal solubility and chemical potential at the transition concentration:
Co-crystal solubility is a function of chemical potential (μ). The chemical potential expression for the equilibrium of co-crystal with solution is:

Aα Bβ = αA(soln) + βB(soln)

µAα Bβ   = α (µAsoln) + β (µBsoln)

At the transition concentration, the solution is saturated with drug (A). The chemical potential of solid drug and drug in solution are equal because they are at equilibrium.

µAsoln = µBsolid

When we consider only one drug substance, µAsolid remains constant and we can substitute µAsolid = C = µAsoln as

                                        µAα Bβ solid   = β (µBsoln) + C                                              (3)

From the above equation it can be concluded that co-crystal solubility is proportional to ligand solubility.[8]

Thermal analysis and predictions of co-crystal solubility (Scc):
Melting temperatures and enthalpies of pharmaceutical crystals have found prevalent utility as indicators of ideal solubility. These are readily measurable properties associated with the crystal lattice energy that must be overcome for dissolution to occur. Among structurally similar pharmaceutical crystalline drug substances, those with high melt temperatures are generally recognized to possess lower solubility. For an ideal solution, the solute solubility, x (mole fraction), is a function of the heat of fusion, melt temperature, and solution temperature.                                                                                                                                              There are a number of considerations when discussing solubility data. The first is equilibrium versus kinetic (or apparent) solubility measurements. Kinetic solubility values are approximate values usually based on one measurement at one time point. For equilibrium solubility, a number of time points and measurements are taken to ensure that the solution has reached equilibrium as evidenced by a plateau in the concentration data. The time required to reach the equilibrium solubility can also be a factor for development based on the residence time in the stomach and intestines. It is desirable to have the drug dissolve while it is in the gastrointestinal tract and very long dissolution times may result in less absorption of the drug. Thus both equilibrium solubility and dissolution rate plays their parts in efficacy of Class-II drugs.
Solubility is a very important parameter to obtain during development of a new compound. As expected, the limited examples in this section show that solubility may be improved using co-crystals, but not in all cases.

Dissolution: Dissolution profile of any active pharmaceutical ingredient (API) represents its bioavailability pattern. The co-crystal dissolution profile is compared with active pharmaceutical ingredient of original in crystal form. Particle size is generally an important and controllable parameter of API forms, including co-crystals, which influences dissolution behavior. Little is known about the effect of the particle size on the dissolution and transformation behavior of a co-crystal. Dissolution studies for pharmaceutical co-crystals were carried out by preparing different co-crystals of same API with different sizes. Powder x-ray diffraction (PXRD) and polarization microscopy are used to study the mechanisms of dissolution improvement from co-crystallization, transformation behavior of each co-crystal in an aqueous suspension. The paddle apparatus is used to study dissolution rate in fasted-state simulated fluid (FaSSIF) at 37 oC. The transformation behavior can be studied by suspending co-crystals of all sizes in FaSSIF at 37 oC. Intrinsic dissolution tests are conducted to compare the dissolution rate of a co-crystal with its host crystal. The sink condition is maintained to study the dissolution rate of API and its co-crystals of different sizes. According to Noyes Whitney equation, the smaller particle sizes dissolved at a higher rate.[19] The dissolution rates for all sizes of co-crystals is nearly similar to that of fine API but variability of the dissolution of co-crystal is greater than that of API. The dissolution rate is influenced by transformation of co-crystal to host crystal or by size reduction or by agglomeration. Particle size reduction increases super saturation state of fine co-crystal and enhance the absorption. The co-crystals are transformed to the host compound form, which is analyzed by using PXRD. The super saturation from the fine co-crystal is faster because of large specific surface area of small particles. While transformation rate of fine co-crystal is slower than that of larger co-crystals. There are three major reasons behind it, (1) The fine and large co-crystals have same surface state i.e. morphology but the larges specific surface area of fine particles require more time for transformation from co-crystal to host crystal. (2) The ratio of major to minor crystal surface area is different between fine and large particles. The large co-crystals mainly consisted of a surface in which guest molecules easily dissociated from the co-crystal.[3] The concentration of guest inside the agglomeration of fine co-crystal increases during co-crystal transformation and guest molecule dissociates.

Bioavailability: Bioavailability is a measurement of the rate and extent of the active drug that reaches systemic circulation. A study with both the parent material and the co-crystal will give a direct assessment of bioavailability improvements due to the co-crystal. A limited number of animal bioavailability studies have been reported using co-crystals. One study on the pharmaceutical co-crystal of a mono phosphate salt with phosphoric acid mentions that excellent in vivo performance was observed, but no details about the study are given.[21]

Stability

Stability is an extensively studied parameter during the development of a new chemical entity. Different types of stability need to be considered depending on the structure and characteristics of the molecule. Chemical and physical stability data are commonly obtained at accelerated stability conditions to determine developability and shelf life. Water uptake is included from a handling and packaging point of view. Thermal stress studies are also incorporated, and extra work may be warranted for hydrates or thermally labile materials. In the case of co-crystals and salts, solution stability may be a factor due to dissociation of the material resulting in precipitation of the less soluble parent compound or a less soluble form. Thus stability studies should be conducted for co-crystals before considering it as viable alternative solid form.

Relative Humidity Stress: Automated moisture sorption/desorption studies are commonly performed to determine problem areas and to provide direction for more detailed studies when the need arises. Significant moisture uptake during the course of the experiment may warrant longer exposure at a specific relative humidity using a relative humidity chamber and subsequent analysis of the sample after equilibration. There is limited water sorption/desorption data present in the literature for co-crystals. One example for a 1:1 indomethacin/saccharin co-crystal showed minimal uptake (<0.05% water) up to 95% RH.[24] The second example for a 1:1 AMG 517/sorbic acid co-crystal again showed a minimal uptake of 0.7% water at 90% RH.[11] These studies showed that relative humidity is not a major concern for these co-crystals; however, longer term studies would be advisable to determine the effects of water under more equilibrium conditions. The well known example of stability improvement via co-crystallization is caffeine co-crystals. Caffeine is known to readily form a hydrate upon exposure to water or water vapor.[25] Six co-crystals were successfully produced: 2:1 caffeine/oxalic acid, 2:1 caffeine/malonic acid, 2:1 caffeine/maleic acid, 1:1 caffeine/maleic acid, and two forms of 1:1 caffeine/glutaric acid. Samples were placed at four RH conditions and analyzed after 1, 3, and 7 days and 7 weeks. The 2:1 caffeine/oxalic acid sample was found to be stable at all RH conditions through 7 weeks. The other co-crystals exhibited behavior similar to caffeine, and one case was found to be worse than caffeine with evidence of dissociation and conversion to caffeine monohydrate. Thus it can be concluded that the strongest acid used (oxalic acid) resulted in the most stable co-crystal, while the weakest acid (glutaric acid) produced the least stable co-crystal.

Thermal stress: High temperature stress is a common condition used to determine chemical and physical stability based on accelerated stability conditions. Very few reports discuss thermal stress experiments on co-crystals. For the co-crystal of a mono phosphate salt with phosphoric acid an eight week exposure at 60 oC resulted in no detectable degradation or form change.[21]
Paracetamol co-crystals of 4,4′-bipyridine, 1,4-dioxane, N-methylmorpholine, morpholine, N,N-dimethylpiperazine, and piperazine were analyzed by differential scanning calorimetry (DSC). The paracetamol/4,4′-bipyridine sample was the only co-crystal that did not lose the guest upon heating and exhibit a melting endotherm corresponding to the monoclinic form of paracetamol where as all other co-crystals did. These limited reports show that heating studies can provide valuable information about physical and chemical stability. Information on elevated temperature transitions can give clues about possible problems in long-term stabilities and can provide guidance on drying steps. These results can be translated into a better understanding of the solid-state system and can help develop more robust compounds and processes.

Chemical stability: Chemical stability is commonly investigated early in the development of a new compound and during formulation studies in order to minimize any chemical degradation that may occur. Very few reports of chemical stability of co-crystals are found in the literature.
In one example, a pharmaceutical co-crystal of a mono phosphate salt with phosphoric acid was reported to have no detectable degradation after 8 weeks of storage at 40 oC/75% RH and 60 oC.[21] Samples of a glutaric acid co-crystal of 2-[4-(4-chloro- 2-fluorphenoxy) phenyl] pyrimidine-4-carboxamide were placed at the same conditions for 2 months, and HPLC impurity analysis did not show any significant increases in known degradants.[20]

Physical stability in solution: Solution stability in this context is defined as the ability of the co-crystal components to stay in solution and not readily crystallize. A variety of vehicles can be used to study solution stability, including water, simulated gastric fluid (SGF), simulated intestinal fluid (SIF), formulation vehicles, and buffered solutions. In many instances, these experiments can be coupled with solubility or dissolution experiments to get a complete understanding of the behavior and the solid form remaining at the end of the experiment. Because dissociation of a co-crystal can occur, solution stability can be a key consideration for development. Studies of co-crystals in water can give an indication of possible dissociation and precipitation of another form such as a hydrate. In the study of caffeine co-crystals, the 2:1 caffeine/ oxalic acid co-crystal was found to be stable at all relative humidity up to 98% RH for 7 weeks.[25]  In order to further test the stability, the material was slurried in water at ambient temperature for 2 days. No change in physical form was observed, demonstrating the stability of the material. A solubility study at pH 7.4 and two buffer strengths (60 and 200 mM) was conducted on an indomethacin/saccharin co-crystal and compared to the γ-form of Indomethacin.[24] At the 60 mM strength, the co-crystal dissolved immediately and was followed by a drop in pH to 6.8 and precipitation of an amorphous material with traces of the α-form of indomethacin. By raising the buffer strength to 200 mM, the co-crystal rapidly dissolved and remained in solution for several hours, giving a 50-fold increase in solubility over the indomethacin γ-form.

Performance comparison of cocrystals of carbamazepine with marketed product


The carbamazepine: saccharin co-crystal was studied in terms of crystal polymorphism, physical stability, in vitro dissolution and oral bioavailability, with the goal of comparing carbamazepine: saccharine co-crystal with the marketed form of carbamazepine (Tegretol®).
Carbamazepine, has a high dose requirement (>100 mg/day) for therapeutic effect. Carbamazepine poses multiple challenges for oral drug delivery, including a narrow therapeutic window, auto induction of metabolism and dissolution-limited bioavailability.[26, 27] Pharmaceutical co-crystals have recently been suggested as promising materials in drug discovery and development.[28] The carbamazepine: saccharin co-crystal has been prepared from methanol solutions and characterized using PXRD, DSC, TGA, microscopy and Raman spectroscopy. The chemical stability of co-crystal was determined using a gradient HPLC technique. Dissolution experiments in SGF were performed using USP dissolution apparatus These studies focused on the initial rate of dissolution, which has been shown to correlate to increased overall absorption and improved bioavailability.[29] As expected, faster initial dissolution was observed with smaller particle size of carbamazepine: saccharine co-crystal, presumably as a result of increased surface area. Sieved co-crystal fractions of particles less than 150 µm showed the fastest initial dissolution. The dissolution rates for sieved fractions greater than 500 µm are slower than that for 150 µm. It is likely that conversion to the di-hydrate on the surface of the larger crystals is responsible for the lower concentrations of carbamazepine observed.
The overall conclusions regarding the stability of carbamazepine: saccharine co-crystals are that (i) chemical stability in the solid-state appears to be similar to the marketed form of carbamazepine, (ii) physical stability of carbamazepine: saccharine co-crystal is comparable to the anhydrous polymorph form which is found in Tegretol® tablet, and (iii) carbamazepine: saccharine co-crystal shows a dependence of dissolution rate on particle size above 150 µm and a resistance of the smaller particle sizes to conversion to di-hydrate in aqueous suspension on the time scale of drug absorption.
For the comparison of bioavailability of carbamazepine: saccharine co-crystal with commercial formulation i.e. Tegretol® tablet, oral pharmacokinetics of carbamazepine: saccharine co-crystal was conducted in dogs. For the purpose of this preliminary pharmacokinetic study, ground 1 (less than 53 µm particle size by microscopy) was mixed with lactose in a dry blending step and placed in HPMC capsules for dosing. In-vitro dissolution experiments carried out on formulated co-crystal containing lactose showed no effect on the rate of dissolution or the concentration of carbamazepine as a result of adding lactose. As per assumed, the co-crystal shows higher plasma levels than Tegretol®, however, no statistically significant differences were observed between pharmacokinetic parameters of Tegretol® and carbamazepine: saccharine co-crystal, as suggested by calculated p values (Student’s t-test).
Thus from overall studies, the benefits of carbamazepine: saccharine co-crystal can be summarized as,
·        Relative lack of polymorphism and equivalent chemical stability to the anhydrous polymorph,
·        Favorable dissolution properties and suspension stability, and
·        Comparable oral absorption profile in dogs compared with the commercial immediate release product.[22]

 

REGULATORY PERSPECTIVE

 

Solid forms of drugs may exhibit undesirable physical properties, but experimental effort can always reveal new forms with potentially advantageous characteristics.[30, 31] Beyond polymorphs, hydrates, salts, and amorphous solids, a thorough solid form screen today may also include a search for co-crystals.[28] Compared to other classes of solid forms, co-crystals possess particular scientific and regulatory advantages, and alongside these advantages are intellectual property issues which confer co-crystals with unique opportunities and challenges.

Pharmaceutical co-crystals, by contrast, have not yet been officially addressed from the perspective of generic regulatory approval. In some respects, co-crystals are intermediate between hydrates (ANDA-eligible) and salts (ANDA-noneligible). Like hydrates, co-crystals are nonionic supra molecular complexes; but like salts, co-crystals involve complexation with substances of greater potential toxicity than water. The issue of whether a new co-crystal of a marketed API may be eligible for regulatory approval via the ANDA mechanism will impact the overall utility of co-crystal technology to the generic pharmaceutical industry, and may possibly bear on the future market place abundance of pharmaceutical products containing co-crystals.[32]

FUTURE PROSPECTS


As compared to salt formation, complexation, micronization, etc. techniques, the co-crystallization is very little explored area. The future development aspects in this area are, polymorphism need to be examined for co-crystals and process to produce co-crystals on a large scale will likely require different approaches, such as those based on ternary solubility phase diagrams. In particular, applying the concepts of supra molecular synthesis and crystal engineering to the development of pharmaceutical co-crystals represents a paradigm that offers many opportunities related to drug development and delivery. It seems inevitable that pharmaceutical co-crystals will gain a broader foothold in drug formulation.

CONCLUSION

On the basis of the limited examples available, it can be concluded on the physicochemical properties of co-crystals that improved solubility for poorly soluble compounds has been achieved using co-crystals. Limited studies suggest that salts will provide a larger increase in solubility if they are available. For poorly soluble neutral compounds, co-crystals are a very feasible approach to improving solubility. Co-crystals 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 co-crystals, even when dissociation of the co-crystal is suspected based on in-vitro studies. Improved stability, such as resistance to hydrate formation, has been shown for co-crystals.

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7.      Blagden N, 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.
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15.  Childs SL, Chyall LJ, Dunlap JT, Smolenskaya VN, Stahly BC, Stahly GP. Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids. J Am Chem Soc 2004, 126,13335-42.
16.  Good DJ, Guez-Hornedo NR. Solubility advantage of pharmaceutical cocrystals. Cryst Growth Dev 2009, 9, 2252-64.
17.  Nehm SJ, Rodriguez-Spong B, Rodriguez-Hornedo N. Phase Solubility Diagrams of Cocrystals Are Explained by Solubility Product and Solution Complexation. Cryst Growth Des 2006, 6, 592-600.
18.  Jayasankar A, Reddy LS, Bethune SJ, Rodriguez-Hornedo N. Role of cocrystal and solution chemistry on the formation and stability of cocrystals with different stoichiometry. Cryst Growth Des 2009, 9,889-897.
19.  Shiraki K, Takata N, Takano R, Hayashi Y, Terada K. Dissolution improvement and the mechanism of the improvement from cocrystallization of poorly water-soluble compounds. Pharm Res 2008, 25,2581-92.
20.  McNamara DP, Childs SL, Giordano J, Iarriccio A, Cassidy J, Shet MS et al. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API Pharm Res 2006, 23,1888-97.
21.  Chen AN, Ellison ME, Peresypkin A, Wenslow RM, Variankaval N, Savarin CG et al. Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid. Chem Commun. (Camb) 2007, 28, 419-21.
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Figure- 1
Co-crystal solubility and the phase solubility diagram[17]
 

               
       Ctr                   Transition concentrations       {Measurable for both cases}
        Case 1             ≤ Drug solubility                    {Measurable}            
        Case 2             ≥ Drug solubility                    {Not always Measurable}
                                       
                                                                                                                                                                                                     
                                                            Case 2 (Supersaturated State)                                                                                                                      
                  Ctr                                                                 Ctr                                                                                                                                                                              
 [Drug]                                                                                                                
                                                                                                                   Drug solubility

                                  Case 1                                                 High solubility crystal
  
                                             
                                                                                    Low solubility crystal
                                                  [Ligand]
















Table- 1
Biopharmaceutical performance of co-crystals
API  or
DRUG


COFORMER
BIOPHARMACEUTICAL PERFORMANCE
REFERENCES

SOLUBILITY

DISSOLUTION

BIOAVAILABILITY
Fluoxetin
Benzoic acid Hydrocloride,
Fumaric acid,
Succinic acid
5.6 mg/ml
11.4 mg/ml
14.8 mg/ml
20.2 mg/ml
-
-
-
-
-
-
-
-

[15]
Itraconazole
Succinic acid, L-malic acid, L- tartaric acid
4 - 20 fold higher than crystalline itraconazole

-

-


[11]
Piroxicam
Saccharin
No improvement
-
-
[11]
2-[4-(4-chloro-2-fluorphenoxy) phenyl] pyrimidine-4-carboxamide




Glutaric acid





-




18 times faster than parent compound





-








[20]
Exemestane
Malic acid
-

Same as API
-

[11]
Megestrol acetate
Saccharin
-

3-4 times higher than API
-


[11]
Celecoxib Form IV
Nicotinamide
-

Faster than Celecoxib Form III

4 times increased

[23]
Fluoxetin HCl
Succinic acid
-

3- fold increase over API
-

[11]
Fluoxetin HCl
Benzoic acid
-

Half- that of API
-

[11]
Fluoxetin HCl
Fumaric acid
-

Same as that of API
-

[11]

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