Method and system for producing a polymorphic or pseudo-polymorphic crystalline phase from a plurality of compounds

Abstract

The invention relates to a method for producing a polymorphic or pseudo-polymorphic crystalline phase from a plurality of compounds (C, D, S1, S2), the method comprising steps of preparing (I) a supersaturated solution from the compounds, homogenizing (II) the supersaturated solution in an ultrasonic bath, transferring (III) the supersaturated solution into a plurality of heated tubes (54), aging (V) the solutions transferred into the tubes for a predetermined period of time, exposing the tubes (54) to a polarized pulsed laser beam before and / or during exposure, followed in situ by nucleation and then growing cocrystals inside the tubes (54), and filtering the exposed solutions in order to recover cocrystals having a size greater than a predetermined minimum size. This method is carried out in order to obtain cocrystallization from at least one active substance (D) and a coformer (C) in at least a first solvent (S1) and a second solvent (S2).

Description

Process and system for producing a polymorphic or pseudo-polymorphic crystalline phase from a plurality of compounds FIELD OF INVENTION

[0001] The present invention relates to a process for producing a polymorphic or pseudo-polymorphic crystalline phase from a plurality of compounds. It also relates to a production system implementing the process according to the invention. TECHNOLOGICAL BACKGROUND

[0002] A laser-induced nucleation technique in supersaturated solutions was discovered by B. Garetz in 1996 using urea in water. It was named NPLIN, for Non-Photochemical Laser-Induced Nucleation. The NPLIN technique allows for temporal and spatial control of nucleation, as well as control of polymorphism. Since nucleation is a rare and stochastic phenomenon, this control enables in situ monitoring of the process and a homogeneous result, for example, crystals all of the same size.

[0003] The document "A New Experimental Setup for High-Throughput Controlled Non-Photochemical Laser-Induced Nucleation: Application to Glycine Crystallization", by Clair B. et al., Journal of Applied Crystallography 47 (August 2014): 1252-60., discloses a nucleation robot allowing an air-solution interface, sample temperature control, and observation by optical microscopy.

[0004] The document "A new cocrystallization method: Non-Photochemical Laser-Induced Nucleation (NPLIN) of a co-crystal of caffeine–gallic acid in water", by Mellah, D. et al., Crystal Growth & Design 2022, 22(10), 5982–5995, discloses a laser-induced nucleation process, in which the dissolution of solutes is carried out in an ultrasonic bath, and solutions are transferred into preheated tubes.

[0005] The document “Experimental Demonstration of the Carbamazepine Crystallization from Non- Photochemical Laser-Induced Nucleation in Acetonitrile and Methanol” by Ikni et al., Cryst. Growth Des. 2014, 14 (7), 3286–3299, discloses a methodology for preparing supersaturated solutions.

[0006] The document “Non-Photochemical Laser-Induced Nucleation of Sulfathiazole in a Water / Ethanol Mixture”, by Li W et al., Cryst. Growth Des. 2016,16 (5), 2514–2526, discloses recommendations for the determination of supersaturation and the preparation of a supersaturated solution by dissolution in an ultrasonic bath.

[0007] Controlling the polymorphism of pharmaceutical products impacts their physicochemical properties as well as the bioavailability of the active ingredients. Each polymorph requires a separate Marketing Authorization (MA) application. One of the main challenges facing the pharmaceutical industry is the limited bioavailability of drugs.

[0008] The pharmaceutical industry has long been interested in crystallization to master the crucial step of API (Active Pharmaceutical Ingredient) crystallization, with the following main characteristics: purification by crystallization, which is the primary objective, obtaining a stable polymorph, and achieving a specific particle size distribution. To achieve this, the widely tested and frequently used method in the pharmaceutical field is seeding, which consists of adding a solid to a supersaturated or saturated medium.

[0009] In this approach, the added polymorph corresponds to the one to be crystallized in the supersaturated medium. The amount of seed, often between 1 and 5% of the mass introduced relative to the total mass of the compound to be crystallized, combined with the seed particle size and the crystallization process (e.g., temperature cooling), determines the final particle size distribution of the crystals. The operating conditions of the crystallization process allow control over the final product quality and the recovery yield.

[0010] The conventional crystallization steps used in the pharmaceutical industries present different disadvantages depending on the situation; they generally all lack control over the timing, precise location or size of the crystals, as well as control over polymorphism.

[0011] In some situations this is not a problem, whereas in others this lack of control has had very significant financial consequences, for example, as in the case of the ritonavir withdrawal. The needs of the pharmaceutical industry differ depending on whether one considers production (control of polymorphism, control of crystal size, control of crystal shape) or research and development (need for an effective method to screen a system).

[0012] The pharmaceutical industry needs precise knowledge of all the characteristics of its compounds. A method capable of directly producing crystals of the required size, without needing additional post-inoculation treatments, is therefore of great interest in the pharmaceutical sector. Obtaining co-crystals and small crystals in a homogeneous distribution would save time and reduce development costs while offering improved physicochemical properties.

[0013] The article "Optical Trapping Controlled Cocrystallization Dynamics of Acetaminophen and l-Phenylalanine," by Wen-Chi Wang et al., Crystal Growth & Design 2024 24 (14), reports continuous-wave laser-induced cocrystallization of two molecules (acetaminophen (Ace) and l-phenylalanine (l-Phe)) in a saturated solvent (deuterated water), with in situ detection achieved by Raman scattering. The authors observed the production of two crystalline forms: a solvate cocrystal with the formula Ace-l-Phe•0.5D2O and an Ace•0D2O crystal. The relative concentration of the two crystalline forms depends on the laser energy and the supersaturation calculated as a function of the exposure time.

[0014] The authors explain that Ace·L-Phe·0.5 D2O crystals are obtained at the laser focal point by optical trapping. Conversely, at relatively higher laser powers, the SS value obtained by optical trapping should be high. Consequently, the high SS value obtained favors the crystallization of pure L-Phe·0 D2O crystals, thus increasing the probability of L-Phe·0 D2O crystal generation because the generation of Ace crystals is strongly limited by optical trapping.

[0015] The authors acknowledge, however, that these discussions lack direct experimental evidence regarding the grouping dynamics during concentration increases. They suggest that another possible explanation for the higher nucleation probability of L-Phe·O D2O crystals at higher laser powers would be that higher laser power leads to greater supersaturation at the laser focus, exceeding the nucleation threshold of L-Phe·O D2O crystals in a 1:1 molar solution of Ace and L-Phe.

[0016] The authors consider it reasonable that, starting from heterogeneous equilibria, the solubility of L-Phe·O₂D₂O crystals should be greater in the 1:1 solution than in the pure D₂O solution due to the eutectic effect. Conversely, the authors believe that relatively low laser powers cannot achieve such high supersaturation, thus decreasing the probability of L-Phe·O₂D₂O crystal generation. However, they observe that neither of the proposed mechanisms can explain the differences in the rates of concentration increase for generated crystals observed during laser irradiation.

[0017] The aim of the present invention is therefore to propose a process for producing a polymorphic crystalline phase, which, unlike prior art processes, can be completely mastered and controlled, thus opening the way to an industrialization of this production.

[0018] This objective is achieved with a process for producing a polymorphic or pseudo-polymorphic crystalline phase from a plurality of compounds, comprising the steps of: preparing a supersaturated solution from said compounds, according to predetermined stoichiometric concentration conditions, homogenizing said supersaturated solution in an ultrasonic bath, according to a predetermined temperature profile, transferring the supersaturated solution into a plurality of heated tubes, aging the solutions transferred in the tubes, for a determined period, exposing said tubes to a pulsed and polarized laser beam, before and / or during exposure, monitoring in situ of nucleation by optical microscopy and then of co-crystal growth inside said tubes, filtering the exposed solutions to recover co-crystals of a size greater than a predetermined minimum size.

[0019] According to the invention, this production process is implemented to carry out co-crystallization from at least one active substance (D) and a co-former (C) in at least one first solvent (S1) and a second solvent (S2) in varying proportions.

[0020] The use of two solvents allows for the generation of new crystalline forms and also offers the possibility of manipulating both the polymorphism and the solubility of the molecules. This helps to balance the solubility differences between the active substance and the co-former, and consequently, to optimize the first preparation step.

[0021] In a particular configuration of the production process of the invention, it further comprises two steps: establishing a phase diagram from the respective physico-chemical characteristics of said active substance (D), said co-former (C), said first solvent (S1) and said second solvent (S2), then determining, from said phase diagram thus established, concentration, temperature and exposure conditions providing a stable form of co-crystals and / or one or more metastable forms of co-crystals.

[0022] In an initial version of this configuration, these steps of establishing a phase diagram and determining the production conditions are carried out prior to the step of exposure to a pulsed laser beam.

[0023] Creating the phase diagram, before exposing the supersaturated solution to the pulsed laser beam, allows the ratios of active substance (D), co-former (C), and the two solvents to be determined. This makes the process faster due to fewer trial-and-error steps.

[0024] In a second version of this configuration, the steps of establishing a phase diagram and determining the production conditions are carried out after the step of exposure to a pulsed laser beam.

[0025] It is then possible to scan the entire phase diagram with the pulsed laser beam in order to determine the stable and metastable phases. This makes it possible to explain the physical mechanisms involved, and could have provided relevant answers to the questions raised by Wen-Chi Wang et al in the aforementioned publication "Optical Trapping Controlled Cocrystallization Dynamics of Acetaminophen and 1-Phenylalanine" published in Crystal Growth & Design 2024 24 (14).

[0026] In a first category of implementation of the process according to the invention, to produce a known co-crystal from an active substance and a co-former having similar solubilities, the determination step includes an identification of temperature and concentration ranges in which the co-crystal is stable.

[0027] In a second category of implementation of the process according to the invention, implemented with an active substance and a co-former having similar solubilities, this process further includes, from the previously established phase diagram, a step of searching for new thermodynamically stable phases possibly including one or more co-crystals.

[0028] In a third category of implementation of the process according to the invention, implemented for the production of a co-crystal whose solubility is already known, this process further includes, from the previously established phase diagram, a step of evaluating the stability of the co-crystal, to determine conditions under which this co-crystal is thermodynamically stable or metastable with respect to the pure active substance and co-former compounds.

[0029] In a fourth category of implementation of the process according to the invention, implemented with an active substance and a co-former having different solubilities, this process further includes, from the previously established phase diagram, a step of identifying composition points where several phases can coexist.

[0030] This step of identifying composition points can advantageously include a detection of coexistence of supersaturated solutions and solid phases.

[0031] Thus, with the production process according to the invention, it is possible to produce co-crystals using the NPLIN technique with significantly reduced nucleation times compared to those observed for spontaneous nucleation. This disruptive approach makes it possible to obtain polymorphic or pseudo-polymorphic crystalline phases on demand.

[0032] The wavelength is chosen so as not to be absorbed by the system in solution (solute (D+C), solvents (S1+S2) or solution (D+C+S1+S2).

[0033] The production process according to the invention offers significant advantages over conventional solution crystallization methods for volumes of a few milliliters. It dramatically reduces the crystallization induction time, with a decrease in the coefficient ranging from 20 to 5600. Furthermore, it offers temporal control and, under certain conditions, spatial control of crystallization, thus enabling the production of new crystalline forms. In other words, the production process according to the invention ensures precise control of the timing, location, and nature of the compound.

[0034] The production process according to the invention could effectively meet the needs of the pharmaceutical industry by enabling the comprehensive and thorough synthesis of all forms of a pharmaceutical active ingredient. This process represents a device that guarantees the control and optimization of crystallization conditions in solution.

[0035] The ability to reliably control and reproduce a process therefore requires a complete and thorough understanding of the API (Active Pharmaceutical Ingredient), including existing and most stable polymorphs. In the pharmaceutical industry, achieving the correct size and particle size distribution is accomplished through grinding, micronization, and other processes, particularly to obtain small crystals with a homogeneous distribution (especially for molecules with very low water solubility, which is often the case for complex organic molecules). A method for directly obtaining small crystals that avoids this processing would be of interest to manufacturers because it would also eliminate this step in the solid-state processing.

[0036] The process according to the invention provides an original solution to certain problems. Our method offers precise control over the timing of nucleation induction, the location and size of the crystals, while significantly reducing the time required for nucleation compared to current methods.

[0037] This definition has been extended to all laser-induced nucleation phenomena (pulsed or continuous, focused or unfocused) of organic (small molecules or proteins) or inorganic compounds. The energy input from the laser also allows for a drastic reduction in the nucleus induction time (nucleus formation). It has also been demonstrated that there is spatial control of nucleation (nucleus localization). By varying the laser polarization, it is possible to achieve (partial or total) control of polymorphism (different crystalline forms of the same molecule).

[0038] Partial polymorphism control has been demonstrated for glycine in water, carbamazepine in acetonitrile and methanol, and sulfathiazole in a water-ethanol mixture. Co-crystals are increasingly used in the pharmaceutical industry due to their potential advantages in terms of drug stability, solubility, and bioavailability. The process has been shown to induce the co-crystallization of two compounds (caffeine and gallic acid in water, and more recently, theophylline and sulfathiazole in water).

[0039] With the production process according to the invention, it is possible to obtain crystallization in a four-component mixture: the two compounds and a solvent mixture in varying proportions. This has made it possible to co-crystallize new hydrates or solvates on demand, thus controlling the nature of the compound.

[0040] A mapping of the impact of experimental parameters on observables (crystal size, nucleation efficiency, desired crystal shape, etc.) was performed by scanning the water percentage. This was verified by creating several ternary phase diagrams in various sections. Eight different co-crystals have already been produced using the manufacturing process according to the invention.

[0041] According to another aspect of the invention, a system is proposed for producing a polymorphic or pseudo-polymorphic crystalline phase from a plurality of compounds, implementing the production process according to the invention, comprising: means for preparing a supersaturated solution from said compounds, under predetermined stoichiometric concentration conditions; means for homogenizing said supersaturated solution according to a predetermined temperature profile; means for receiving a plurality of tubes, each intended to receive a fraction of said supersaturated and homogenized solution; means for aging said fractions of solution contained in said tubes for a predetermined aging period; means for exposing said tubes to a pulsed and polarized laser beam; means for monitoring in situ, before and / or during exposure, the nucleation and growth of co-crystals inside said tubes.means to filter the exposed solutions, so as to recover co-crystals larger than a predetermined minimum size.

[0042] According to the invention, this production system is arranged to carry out co-crystallization from at least one active substance (D) and a co-former (C) in at least one first solvent (S1) and a second solvent (S2) in varying proportions.

[0043] In a particular configuration of the invention, the system further comprises: means for establishing a phase diagram from the respective physicochemical characteristics of said active substance (D), said co-former (C), said first solvent (S1) and said second solvent (S2), and means for determining, from said phase diagram thus established, concentration, temperature and exposure conditions providing a stable form of co-crystal production and / or one or more metastable forms of co-crystals

[0044] The receiving means for the tubes may advantageously include a sample-carousel.

[0045] Homogenization methods may include a thermostatically controlled ultrasonic bath.

[0046] The monitoring methods can include a microscope equipped with a camera.

[0047] Laser exposure means may include an optical system for directing a polarized laser beam to a tube arranged on the sample carousel.

[0048] The production process according to the invention can, by way of non-limiting example, be applied for the production of thermodynamically stable or metastable co-crystals from caffeine and gallic acid in water and methanol. DESCRIPTION OF THE FIGURES

[0049] Figure 1 represents an example of a ternary phase diagram implemented in the present invention, in 1:1 stoichiometry and in x>1:1 stoichiometry; Figure 2 schematically illustrates an example of an embodiment of a production system for a polymorphic or pseudo-polymorphic crystalline phase according to the invention; Figure 3 schematically illustrates an example of an embodiment of a robotic carousel implemented in the production system; Figure 4 illustrates an example of a sequence of steps implemented in a production process according to the invention; Figure 5 schematically illustrates an example of an embodiment of an ultrasonic bath used for the preparation of a supersaturated solution in a production system according to the invention; Figure 6 represents experimental supersaturation points carried out in NPLIN on the CAF-GAL ternary water diagram;Lare represents experimental supersaturation points as well as the different percentages of water represented by black dotted lines on the ternary diagram CAF-2GAL_eau_MeOH; and Lare represents an example of a (concentration-temperature) diagram illustrating the effects of the NPLIN technique on the realization of metastable forms. DETAILED DESCRIPTION

[0050] As previously stated, in a particular configuration of the production process according to the invention, the latter further comprises establishing a ternary phase diagram for an assembly consisting of an active substance D, a co-former C, a solvent S, and a liquid L, which can be carried out using techniques well known in the field of physical chemistry. For example, reference can be made to the website https: / / chemostratigraphy.com / how-to-plot-a-ternary-diagram-in-excel / , which describes a technique for plotting a ternary diagram in an Excel® spreadsheet.

[0051] We will first describe, with reference to Figures 2 and 3, an example of an embodiment of a production system S according to the invention. This system S comprises a laser source 1 emitting a continuous or pulsed laser beam, which passes through a first optical device 11 associated with a power measuring instrument 2, a quarter-wave plate to achieve circular polarization and a long focal length lens 3 to a mirror 4 intended to direct the laser beam towards a laser exposure zone at the level of a sample-carrying carousel 5 comprising a motorized platform arranged on a stage 53 and intended to receive 90 tubes 54 each containing a fraction of the supersaturated solution.

[0052] The pulsed, ring-shaped laser beam is generated by the 1 Nd Q-switched laser source, producing a train of ten pulses per second, with linear or circular polarization, a pulse width of 7 ns, and a wavelength of 532 nm. A wavelength of 1064 nm is also possible.

[0053] The sample carousel 5, which is kept at temperature by means of a thermostatically controlled bath and a back-and-forth circulation 7,8 of a fluid, is rotated to expose the 90 tubes one by one to the laser beam.

[0054] The various parameters of the laser 1 used to irradiate the tubes 54 can vary: linear or circular polarization of the laser (LP or CP), a power between 0.2 and 0.9 GW / cm², and an exposure time from 1 pulse to 100 pulses. Each tube 54 is observed using an inverted microscope 6, and in situ photomicrographs were taken using a CCD camera 10 connected to the microscope 6 to monitor the evolution of crystallization within the tubes.

[0055] We will now describe, with reference to figures 4 and 5, steps of the NPLIN process implemented in the production process according to the invention.

[0056] In a first step I, a saturated solution 61 containing a solvent S, a liquid L, an active substance D and a co-former C, is prepared in a container 62 at a temperature T1.

[0057] This container 62 is then placed (step II) in an ultrasonic bath 63 equipped with heating elements 65, 66 and ultrasonic generators 67, 68, to dissolve and homogenize the solution over a period of 24 to 30 hours. The temperature of the solution is then raised to a temperature T2 higher than the preparation temperature T1.

[0058] The solution is then distributed into 90 tubes arranged in carousel 5. In step III, lasting 5 to 6 hours, the tubes filled with the solution are maintained at temperature T2 and then cooled in a cooling step IV to return to the initial temperature T1. This is followed (step V) by an aging phase to allow cluster formation, lasting 12 hours, after which each tube is exposed to pulsed laser irradiation – from 1 to 100 pulses – which triggers a nucleation process (step VI) lasting 10 minutes to one hour, then co-crystal growth (step VII) lasting 12 to 48 hours, during which the contents of the tubes are filtered to extract the co-crystals, which are then characterized (step VIII).

[0059] Once the crystal reaches a sufficient size, the solution is filtered. It is then possible to proceed with the ex situ characterization steps as needed (step VIII).

[0060] Nucleation is monitored in situ by regularly recording photographs of each of the tubes, using camera 10 connected to microscope 6.

[0061] To carry out the NPLIN technique (for reminder: Non Photochemical Laser Induced Nucleation), which is at the heart of the production process according to the invention, several parameters related to the laser and the solution must be taken into consideration, including the establishment of the phase diagram, which is however not a necessary condition for carrying out the laser-induced nucleation process: an appropriate choice of the stoichiometry of the compounds in the supersaturated solution is essential, requiring the determination of the solubility of the pure compounds or the co-crystal in the chosen solvent; it is crucial to define the limit of the metastable zone to ensure that the crystallization is indeed induced by the laser and not spontaneous; the solubilization conditions must be optimized to obtain a clear solution, eliminating any presence of solid particles before the execution of the steps of the NPLIN technique.This includes managing dissolution times, maximum dissolution temperature, cooling rate and experiment temperature; manipulating parameters such as energy density, exposure time, polarization or laser wavelength is necessary to control the laser-induced crystallization process; once the crystal has reached a sufficient size, various characterization techniques are used to analyze it.

[0062] We will now describe different categories of implementation of the production process according to the invention, with regard to the phase diagram.

[0063] The co-crystallization configurations using the NPLIN technique implemented in the production process according to the invention can be classified into four categories: Category 1: The solubilities of the active pharmaceutical substance (APS) and the coformer are similar, and the co-crystal is known. Category 2: The solubilities of the APS and the coformer are similar, but the existence of the co-crystal remains to be demonstrated. Category 3: The solubility of the co-crystal is already known. Category 4: The solubilities of the compounds are considerably different, leading to an incongruent ternary diagram, where the crystallization of the co-crystal is influenced by complex factors due to the differences in solubility.

[0064] The use of phase diagrams in the context of pharmaceutical co-crystals is essential for understanding the crystallization process. A phase diagram is a 2D or 3D graphical representation that shows the composition in which the different phases of a system are thermodynamically stable at a given temperature and pressure. These diagrams can be used for each category described previously.

[0065] The preliminary steps of establishing the phase diagram and determining the operating conditions are carried out once per system (solvent(s) + solute(s)), while steps I to VIII concern a maximum of 90 tubes per measurement point, i.e. about 1 week for 100 ml of supersaturated solution.

[0066] Category 1: Similar solubilities and known co-crystal

[0067] For systems where the solubility of the active substance and the co-former is similar and the co-crystal is known, the phase diagram is generally congruent. In this case, the phase diagram can be used to determine and optimize the co-crystal formation conditions using the NPLIN method: identifying the temperature and concentration ranges where the co-crystal is stable.

[0068] Category 2: Similar solubilities and co-crystal not demonstrated

[0069] In this case, although the solubilities are similar, the existence of the co-crystal remains to be demonstrated. The phase diagram can be designed and explored with the aim of: searching for new thermodynamically stable phases: investigating temperature and concentration conditions to detect the potential formation of new phases, including co-crystals; determining experimental conditions: performing NPLIN crystallization tests under different conditions to confirm the existence of the most thermodynamically stable co-crystal and to verify whether the NPLIN technique allows the co-crystallization of other metastable forms. Category 3: Solubility of the co-crystal known

[0070] When the solubility of the co-crystal is already known, the phase diagram is essential to assess stability, and to determine the conditions under which the co-crystal is thermodynamically stable or metastable relative to pure compounds.

[0071] Category 4: Different solubilities and incongruent ternary diagram

[0072] For systems with very different solubilities, the phase diagram is often incongruent ternary, which implies increased complexity of crystallization processes: Identify composition points where several phases can coexist, including supersaturated solutions and solid phases.

[0073] In all these categories, phase diagrams provide information either for the optimization of co-crystal formulation or for the study of co-crystal stability.

[0074] Regardless of the categories mentioned above, phase diagrams can be determined by conventional methods before the NPLIN process. This allows for establishing the NPLIN conditions necessary to obtain the stable phase and to determine if other metastable phases exist. They can also be determined afterward to identify the stable form if multiple forms were obtained by NPLIN. Furthermore, the NPLIN technique allows for easy and precise scanning of the entire quaternary diagram.

[0075] In preliminary steps of establishing the ternary phase diagram and determining the operating conditions of the NPLIN process, a solubility study of the compounds is carried out and the crystallization zone of each compound is determined. Practical examples of co-crystal production

[0076] By applying the production process according to the invention to a caffeine-gallic acid system, six new crystalline forms were identified, whereas only three had previously been reported in the literature. Analysis of the ternary phase diagrams revealed that only three of the co-crystals are thermodynamically the most stable, with a wide crystallization range.

[0077] It was observed, with the caffeine-gallic acid-water system, that the production process according to the invention allowed for the co-crystallization of the most stable forms, with reference to the. However, in the caffeine-gallic acid-water-methanol system with a stoichiometry of 1:2, the production process according to the invention led to the formation of different crystalline forms, including CAF-GAL•0H2O, CAF-GAL•2MeOH, CAF-GAL•1MeOH•1H2O, CAF-GAL•0.5H2O form I and CAF-GAL•0.5H2O form III, with reference to the.

[0078] Under these conditions, the most stable form is CAF-GAL•1MeOH•1H2O, present across the entire range of water percentages tested. At 1% water, three forms are obtained: CAF-GAL•0H2O, CAF-GAL•1MeOH•1H2O, and CAF-GAL•2MeOH. At 25% water, three forms are obtained with 100 pulses (CAF-GAL•1MeOH•1H2O, CAF-GAL•0.5H2O form I, and CAF-GAL•0.5H2O form III). The ternary diagram indicates that between 1% and 25% water, only the CAF-GAL•1MeOH•1H2O form exists, leading to the conclusion that NPLIN nucleation can co-crystallize not only the most stable phases but also metastable forms, which is of interest to the pharmaceutical industry.

[0079] Mastering phase diagrams allows for the accurate determination of the stoichiometry and crystallization zone of desired compounds. Conversely, the NPLIN technique also allows for the exploration of the phase diagram and a deeper study of the different crystalline forms of a given system, making it a highly effective tool for screening various crystalline forms of a drug.

[0080] Among the many applications of crystallization in fine chemicals, the pharmaceutical industry represents the largest. Approximately 80% of pharmaceutical products require at least one crystallization step, primarily for the purification of intermediates and active pharmaceutical ingredients (APIs). With the anticipated increase in the number of new drugs in development in the coming years, the need for tighter control over their properties is increasing the demand for crystallization.

[0081] When the solubility of the co-crystal is unknown and its existence needs to be demonstrated, the first step is to determine the supersaturation and the dissolution protocol. Next, the irradiation conditions, the aging time required to trigger nucleation, and the solution parameters necessary to induce nucleation using the NPLIN technique are established, with reference to the figure representing a concentration-temperature curve. In this figure, increasing concentration levels are associated with successive laser pulses 1, 2, ..., n, until a metastable form is reached.

[0082] Experimental results obtained show that the NPLIN technique implemented in the production process according to the invention makes it possible to crystallize metastable forms, which cannot be revealed by classical phase diagrams and thermodynamically stable forms.

[0083] The first step involves determining the supersaturation and the dissolution protocol. Next, the aim is to establish the irradiation conditions, the aging time required to trigger nucleation, and the solution parameters necessary to induce nucleation using the NPLIN technique.

[0084] The results obtained show that the NPLIN technique allows the crystallization of metastable forms, which cannot be revealed by classical phase diagrams, and of thermodynamically stable forms. The NPLIN technique is an effective tool for exploring the entire system, constructing a phase diagram, and accessing all possible forms, whether stable, hydrated, solvated, or even thermodynamically unstable. Furthermore, this approach allows for better control of the stochastic nature of the crystallization process by directing the formation of the desired phases.

[0085] The production process according to the invention constitutes an effective tool for exploring the entire co-crystallization system, constructing a phase diagram, and accessing all possible forms, whether stable, hydrated, solvated, or even thermodynamically unstable. Furthermore, this approach allows for better control of the stochastic nature of the crystallization phenomenon by guiding the formation of the desired phases.

[0086] Of course, the present invention is not limited to the examples just described, and many other embodiments can be envisaged without departing from the scope of the invention.

Claims

A process for producing a polymorphic or pseudo-polymorphic crystalline phase from a plurality of compounds (C, D, S1, S2), comprising the steps of: preparing (I) a supersaturated solution from said compounds under predetermined stoichiometric concentration conditions; homogenizing (II) said supersaturated solution in an ultrasonic bath under a predetermined temperature profile; transferring (III) the supersaturated solution into a plurality of heated tubes (54); aging (V) the solutions transferred into the tubes for a predetermined period; exposing said tubes (54) to a pulsed, polarized laser beam before and / or during exposure; monitoring nucleation by optical microscopy and then co-crystal growth within said tubes (54); and filtering the exposed solutions to recover co-crystals larger than a predetermined minimum size.characterized in that it is implemented to carry out co-crystallization from at least one active substance (D) and a co-former (C) in at least one first solvent (S1) and a second solvent (S2) in varying proportions. A process according to the preceding claim, characterized in that it further comprises two steps: establishing a phase diagram from the respective physicochemical characteristics of said active substance (D), said co-former (C), said first solvent (S1) and said second solvent (S2), and then determining, from said phase diagram thus established, concentration, temperature and exposure conditions providing, at the end of the aforementioned production steps, a stable form of co-crystals and / or one or more metastable forms of co-crystals. A method according to the preceding claim, characterized in that the steps of establishing a phase diagram and determining the production conditions are carried out prior to the step of exposure to a pulsed laser beam. A method according to claim 2, characterized in that the steps of establishing a phase diagram and determining the production conditions are carried out after the step of exposure to a pulsed laser beam. Method (1) according to any one of claims 2 to 4, implemented to produce a known co-crystal from an active substance and a co-former having similar solubilities, characterized in that the determination step includes an identification of temperature and concentration ranges in which the co-crystal is stable. Method (2) according to claim 3, implemented with an active substance and a co-former having similar solubilities, characterized in that it further comprises, from the previously established phase diagram, a step of searching for new thermodynamically stable or metastable phases possibly including one or more co-crystals. Method (3) according to claim 3, implemented for the production of a co-crystal whose solubility is already known, characterized in that it further comprises, from the previously established phase diagram, a step of evaluating the stability of said co-crystal, to determine conditions under which said co-crystal is thermodynamically stable or metastable with respect to the pure active substance and co-former compounds. Method (4) according to claim 3, implemented with an active substance and a co-former having different solubilities, characterized in that it further comprises, from the previously established phase diagram, a step of identifying composition points where several phases can coexist. Method (4) according to the preceding claim, characterized in that the step of identifying composition points includes a detection of coexistence of supersaturated solutions and solid phases. System (S) for producing a polymorphic or pseudo-polymorphic crystalline phase from a plurality of compounds (C, D, S1, S2), implementing the production process according to any one of the preceding claims, comprising: means for preparing a supersaturated solution (61) from said compounds, under predetermined stoichiometric concentration conditions; means (60) for homogenizing said supersaturated solution according to a predetermined temperature profile; means (5) for receiving a plurality of tubes (54), each intended to receive a fraction of said supersaturated and homogenized solution; means for aging said fractions of solution contained in said tubes (54) for a predetermined aging period; means (1, 3, 4) for exposing said tubes (54) to a pulsed and polarized laser beam; means (6, 10) for monitoring in situ by optical microscopy, before and / or during exposure.the nucleation and growth of co-crystals inside said tubes (54), means for filtering the exposed solutions so as to recover co-crystals larger than a predetermined minimum size, characterized in that it is arranged to carry out co-crystallization from at least one active substance (D) and a co-former (C) in at least one first solvent (S1) and a second solvent (S2,L) in varying proportions. Production system according to the preceding claim, characterized in that it further comprises: means for establishing a phase diagram from the respective physico-chemical characteristics of said active substance (D), said co-former (C), said first solvent (S1) and said second solvent (S2), and means for determining, from said phase diagram thus established, concentration, temperature and exposure conditions providing, at the end of the aforementioned production steps, a stable form of co-crystals and / or one or more metastable forms of co-crystals. Production system (S) according to one of the two preceding claims, characterized in that the tube receiving means comprise a sample-carrying carousel (5). Production system (S) according to one of the three preceding claims, characterized in that the homogenization means comprise a thermostatically controlled ultrasonic bath (60). Production system (S) according to one of the four preceding claims, characterized in that the in situ monitoring means comprise a microscope (6) equipped with a camera (10). Production system (S) according to any one of the five preceding claims, characterized in that the laser exposure means comprise an optical system for directing a polarized laser beam to a tube (54) disposed on the sample-carrying carousel (5). Application of the production process according to any one of claims 1 to 9, for the production of thermodynamically stable or metastable co-crystals from caffeine and gallic acid in water and methanol.

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