A Study On The Polymorphism Of Piroxicam In Solution And In Melt

Polymorph is a phenomenon that one substance could exit in different structures.It is estimated that 37-66%of organic molecules have polymorph.Polymorph is also common in drug molecules which could affect the properties of drugs,such as solubility,dissolution rate and tabletability.Consequently,polymorph discovery is regarded as an essential step for the pharmaceutical industry.The polymorph screen method could be roughly divided into solution crystallization and melt crystallization.Solution crystallization is the most common method to screen polymorphs,including cooling crystallization and evaporation crystallization and so on.Recently,more and more metastable polymorphs have been discovered by melt crystallization,making the melt crystallization become an important complement to solution crystallization in polymorph discovery.Meanwhile,there has been steady progress of the crystal structure prediction(CSP),successfully predicting polymorphs observed in the laboratory.However,an issue at the current stage of development is that computers predict far more structures than those found experimentally,and it is unclear whether the discrepancy results are from a failure to remove implausible structures by the CSP,a failure to discover polymorphs in the lab,or both.In this context,the comparison between experimental and predicted structures is significant to improve the accuracy of CSP.On the other hand,the improvement of CSP could better guide the polymorph discovery in experiments.The stability evaluation of polymorph is also important.According to the Ostwald's rule,the metastable form could transform to a relatively stable form to lower free energy.Phase transformation is a double-edged sword in the pharmaceutical industry.On the one hand,the unexpected phase transformation of drugs could cause incalculable losses.On the other hand,phase transformation could provide an effective method for polymorph discovery.Solution-mediated phase transformation(SMPT)is an effective technique to produce the final stable form for the pharmaceutical industry.Sometimes,two or more polymorphs would crystallize simultaneously under the same conditions,which is called concomitant crystallization.The concomitant crystallization also could occur during the SMPT process which will affect the quality and even safety of a drug product.It is very important to adjust the thermodynamic and kinetic parameters of SMPT to repeatedly and consistently produce the pure form with the robust procedure.In this thesis,piroxicam is selected as a model drug to study the polymorph in melt and phase transformation in solution.Two new polymorphs of piroxicam(forms? and ?)were discovered in melt and the energy characteristics of polymorphs discovered by melt crystallization were explored.Besides,the nucleation and growth kinetics of piroxicam polymorphs were studied in-depth to provide theoretical guidance for the polymorph discovery by melt crystallization.Because of the similar energy of form ? and form ?,the piroxicam monohydrate could transform to form ?and form ? simultaneously.By adding additives or adjusting the particle size of piroxicam monohydrate,we could control the outcomes of the SMPT of piroxicam monohydrate,selectively obtaining the form ? or form ?.The mechanisms of SMPT under different conditions were also investigated.The main contents are as follow:1.New Polymorphs Discovered by Melt Crystallization and Crystal StructurePrediction Two new polymorphs of piroxicam(forms ? and ?)were discovered by melt crystallization and crystal structure prediction(CSP).High-quality single crystals were grown from melt microdroplets for structural solution by X-ray diffraction.Relative to the previously known polymorphs obtained mainly by solution crystallization,the new polymorphs are thermodynamically less stable,confirming melt crystallization as an important complement to solution crystallization in polymorph discovery.Although early workers reported that piroxicam is thermally unstable and unsuitable for melt crystallization,our use of melt microdroplets circumvented this problem.Our CSP identified all known polymorphs of piroxicam including the two new forms with an energy ranking in reasonable agreement with the observed order,as well as low-energy structures not observed by experiment.2.The Nucleation and Growth Kinetics of Piroxicam Polymorphs in the Melt.The nucleation and growth kinetics of piroxicam polymorphs have been investigated separately in the melt.To crystal growth,all piroxicam forms studied in this work show similar growth rates in the diffusion-controlled mode.Compared to growth,nucleation rates are vastly different,exhibiting the polymorph selection.Only forms ? and ?could nucleate from the melt under the limited experiment time and the nucleation rate J of forms ? and VI reaches a maximum of?107 m-3s-1 and 109 m-3s-1,respectively.Meanwhile,the maximum nucleation rates Jmax of other forms were estimated to?104 m-3s-1.The classical nucleation theory(CNT)describes our data reasonably well,yielding interfacial free energy ?=0.011 J/m2 for form ? and 0.013 J/m2 for form ?,indicating the faster nucleation rate of form ? is related to its smaller interfacial energy.It also indicates the reason why forms ? and ? could spontaneously crystallize from the melt,while the nucleation of other forms must depend on cross nucleation or seedings.3.The Effect of Hydroxyl-Containing Additives on the Solution-Mediated Phase Transformation of Piroxicam OutcomeSolution-mediated concomitant phase transformation(SMCPT)of the piroxicam monohydrate was found.The piroxicam monohydrate could simultaneously transform to block form ? and needle form ? in acetone at 31?.However,the form ? and the form ? can be selectively grown in the presence of 0.04 mg/mL hydroxyp ropyl cellulose(HPC)and 1%H2O,respectively.In addition,the morphology of form ? is changed from block to rod-like or even needle with the increase of the concentration of HPC.Based on these phenomena,the roles of HPC and H2O in the solution-mediated concomitant phase transformation were studied.The mechanisms of HPC and H2O to affect the process of SMCPT of the piroxicam monohydrate are different.In the presence of 0.04 mg/mL HPC,the interaction between the HPC molecules and the piroxicam molecules was the main factor that governed the process of SMCPT of the piroxicam monohydrate.However,in the presence of H2O,the driving force of SMCPT played the main role.In our work,the outcome of SMCPT could be tuned directly by additives for the first time,which provides a good guide to obtain the pure polymorph in the SMCPT for the pharmaceutical industry.4.Size-dependent Solution-Mediated Phase Transformation of Piroxicam Monohydrate ParticlesThe size effect on the solution-mediated phase transformation(SMPT)outcome of piroxicam monohydrate particles(PMPs)has been investigated among five sizes(0.38 ?m,3 ?m,14 ?m,44 ?m,104 ?m,average size).Different SMPT outcomes of piroxicam monohydrate were achieved by adjusting the particle size itself.As the size of PMPs increases from 0.38 ?m to 104 ?m,the SMPT outcome of piroxicam monohydrate is changed from form ? to form ? and form ? coexisting to form ?.To understand the SMPT mechanism of piroxicam monohydrate affected by the particle size,we have monitored the concentration of piroxicam during the SMPT process by ex-situ High Performance Liquid Chromatography(HPLC)method and the SMPT process by in-situ microscopic observation.Different particle sizes of piroxicam monohydrate have different dissolution rates which could affect both the maximum concentration of piroxicam during the SMPT process and the heterogeneous nucleation,finally determining the SMPT outcome of piroxicam monohydrate.