| The presence of polymorphism in solid materials is a very common phenomenon.More than 80%of drugs are solid and often exist in crystal form.Different polymorphism of drug will cause significant changes in their physical and chemical properties.The pharmaceutical properties,including the solubility,dissolution rate,stability,which are greatly influenced by their polymorphism,have a directly effect on the bioavailability,safety and efficiency of the drug product.The study of drug polymorphism involving the interdisciplinary fields such as pharmacology,chemical engineering,thermodynamics and kinetics of crystal nucleation and crystal growth is also an important part in pharmaceutical industries.In addition,the control of drug morphology is also the focus of drug quality control.The slender needle and soft fibrous morphology of crystals will not only bring inconvenience in the characterization,but also affect the processing and production of drug.The morphology and polymorph control play an important role in drug development and has been paid more and more attention by enterprises and researchers in recent years.The traditional crystallization methods are not enough for the polymorph and morphology control.So many non-traditional crystallization methods emerge.However,some non-traditional crystallization methods are implemented under harsh conditions and complex operations,thus,more and more researchers devote to explore a simple and efficient method for controlling the polymorph and morphology.The mechanism of polymorph and morphology control was also explored.The study of the mechanism is helpful for us to select suitable methods for polymorph screening,so as to improve the efficiency of the controlling the polymorph and morphology.In addition,concomitant crystallization is a common phenomenon in the polymorph screening.It is hard to get the pure form with high repeatability,which affects the subsequent process of filtration,drying and transportation of drugs as well as the therapeutic effect of drugs.Therefore,a robust procedure to repeatedly and consistently produce the pure material is in urgent need for drug quality control.In this work,the polymorph and morphology of acetaminophen(ACM)and sulfathiazole(STZ)in the presence of foreign interfaces(hydrogel and two-dimensional layered material MoTe2)were studied.The concomitant crystallization of STZ are avoided and the mechanisms were also explored.The main contents of this dissertation are as follows(1)Controlled Morphology Evolution of Acetaminophen Trihydrate(ACMTC)Crystals in GelatinThe unstable ACMTC precipitated via swift cooling crystallization in ACM saturated solution,and the morphology of ACMTC was soft fibrous like.We explored the effect of gelatin concentration on the morphology evolution of ACMTC(1)At lower concentration of gelatin(0.1 wt%- 0.7 wt%),the morphology of ACMTC crystals was regular long rod like.With the increasing of gelatin concentration to 0.7 wt%,the length of ACMTC along the b-axis direction,which was the visible direction under the microscope,increased by more than 10 times.However,the MSZW of ACMTC crystals also gradually widen with the increase of gelatin concentration,and the induction time was increased by more than three times All these indicate that the nucleation of ACMTC crystals can be effectively inhibited with the increase of gelatin concentration.The growth rate of ACMTC crystal along a-axis and b-axis was measured,and it was found that the growth rate of ACMTC crystal along a-axis was decreased by nearly 190 times,and the growth rate along b-axis was decreased by nearly 70 times.Under this concentration range of gelation,the morphology change of ACMTC crystal was due to the inhibition effect of gelatin on ACMTC crystal nucleation and growth.Reduction of nucleation number enabled ACMTC crystals to have a continuous supply of solute during the growth process,which can keep the growth of bigger ACMTC.Finally,the volume of ACMTC crystal also increased significantly.(2)At higher concentration of gelatin(>0.7 wt%),the morphology of ACMTC crystals gradually changed into dendrite,and the number of nucleation decreased obviously,but the MSZW of ACMTC did not change with the increase of gelatin concentration.The solution was losing its mobility.At this concentration range,the evolution of morphology is mainly affected by the diffusion limiting process of the three-dimensional network structure of gelatin.The results can provide a simple and effective method to improve the morphology and quality of the slender needle or soft fibrous like crystals(2)Polymorphic Control of Sulfathiazole(STZ)in Agarose GelIn this work,crystallization of STZ at supersaturation of 4.85 was taken as an example to carry out the research.Under this supersaturation condition,Form Ⅱ,Form Ⅲ and Form Ⅳ of STZ crystallized simultaneously by cooling crystallization method without any additive.When we added agarose to the solution of STZ,it was found that the pure Form Ⅲ and Form Ⅳ could be easily obtained respectively by changing the concentration of agarose.Interestingly,during this period,the phenomenon of cross-nucleation between Form Ⅲ and Form Ⅳ was found for the first time in solution by adjusting agarose concentration.The screening mechanism of STZ polymorph at different agarose concentrations was explored in detailed.The main conclusions are as follows:(1)At a lower concentration of agarose(<0.006 wt%),the pure Form Ⅳ was obtained.The agarose in solution still adopted single-coil conformation,which made a large number of hydroxyl groups exposed to solution.These hydroxyl groups disrupted the recognition of hydrogen bonds between Form Ⅱ and Form Ⅲ,eventually,only Form Ⅳ was formed.(2)At a higher concentration range of agarose(～0.05 wt%-3.26 wt%),the pure Form Ⅲ was produced.At this time,the helix chains of agarose may combine to form a three-dimensional porous network in solution.The presence of network would reduce the mobility of the solute molecules,which lead to decrease the solute concentration in the meshes.Finally,Form Ⅲ with the lowest nucleation barrier was appeared.(3)When the concentration of agarose was in a medium range(-0.01 wt% 0.04 wt%),during the crystallization process of STZ,the phenomenon of cross-nucleation between Form Ⅲ and Form Ⅳ occurred.At this point,the low concentration regions(rich in solvent)and more highly concentrated regions(rich in biopolymer)were formed within agarose network.The occurrence of this phenomenon and the induction of hydroxyl groups on the agarose chain together led to the formation of heterogeneous structures(Form Ⅲ and Form Ⅳ)(3)Polymorphic Control by 2D layered material MoTe2The polymorphic control of ACM and STZ on 2D layered material MoTe2 was investigated.The main conclusions are as follows:(1)Without MoTe2,Form Ⅰ of ACM crystallized by cooling crystallization.When MoTe2 was added to ACM supersaturated solution,the formation of Form Ⅱ was significantly promoted after cooling crystallization.It was found that Form Ⅱ grew on the crystal surface of MoTe2 along a-axis,and the nucleation time of Form Ⅱ was significantly shortened,but the morphology of the crystal did not change.Through the addition of other heterogeneous templates,it is found that only two-dimensional materials induce the formation of Form Ⅱ.(2)Without MoTe2,Form Ⅱ,Form Ⅲ and Form Ⅳ of STZ crystallized by cooling crystallization.When MoTe2 was added to STZ supersaturated solution,the formation of Form Ⅳ was significantly promoted after cooling crystallization.However,Form Ⅳ did not grow on the crystal surface of MoTe2.The nucleation time of Form Ⅳ was significantly longer than that without MoTe2,and the morphology of Form IV also changed.We compared the crystal arrangement on specific crystal planes in order to understand the mechanism.It was found that the nucleation of Form Ⅳ was mainly induced by interaction of van der Waals forces between MoTe2 and the specific crystal surface of Form Ⅳ.When MoTe2 added to STZ supersaturated solution,the length of Form Ⅳ along the c-axis was significantly shortened,but the length along the b-axis was increased.This was due mainly to the crystal faces along the direction of the c-axis adsorbed MoTe2 through the interaction of van der Waals forces,which hindered the growth of the crystal along the direction of the c-axis.However,the crystal faces along the b-axis had a large number of intermolecular hydrogen bonds,which was conducive to the interaction of STZ-STZ through hydrogen bonds.Therefore,Form Ⅳ would grow along the b-axis and eventually lead to the change of Form Ⅳ morphology.In the process of polymorph and morphology control,MoTe2 was equivalent to insoluble additive.(3)MoTe2 also had obvious screening effect on some pharmaceutical polymorphism(isonicotinamide,indomethacin and Isonicotinamide-Carbamazepine co-crystal)which preferred orientation faces had only van der Waals force. |
PDF Full Text Request