Solution-mediated Phase Transformation Research Articles

Solid Forms of Bio-Based Monomer Salts for Polyamide 512 and Their Effect on Polymer Properties

Polyamides’ properties are greatly influenced by the polymerization process and the type of feedstock used. The solid forms of nylon salts play a significant role in determining the final characteristics of the material. This study focuses on the long-chain bio-nylon 512. Firstly, we systematically investigated the possible solid forms of the nylon 512 salt, including crystal forms and morphologies, by massive experimental screening, single-crystal X-ray diffraction, Hirshfeld surface analysis, and TG-DSC measurements. The regulation and control of the various solid forms were achieved through solid-state transformations (SSTs) and solution-mediated phase transformations (SMPTs). Our findings shows that the nylon 512 salt exists in two crystal forms (anhydrate and dihydrate) and four morphologies (needle-like, plate-like, rod-like, and massive block crystal). Many factors will influence the formation of these solid forms, such as water activity, temperature, solvent, and ultrasonic physical fields. We can choose the right factors to regulate this as needed. On this basis, we studied the effects of different solid forms (crystal forms and morphologies) on the properties of the resulting polyamides prepared using direct solid-state polymerization (DSSP). The solid form of the salt had many effects on the polymer, including its structure, melting point, and mechanical properties. The polyamide obtained through DSSP of the anhydrate salt exhibited a higher melting point (204.22 °C) and greater elastic modulus (3.366 GPa) compared to that of the dihydrate salt, especially for the anhydrate salt of plate-like crystals.

Comprehensive exploration of riboflavin solid forms and preparation mechanism of stable forms

Riboflavin is a water-soluble vitamin regarded as an essential nutrient participating in biological oxidation in vivo. The strong hygroscopicity and crystalline phase impurity of riboflavin in the solid state are obstacles to its industrial production and storage. Riboflavin is polymorphic and is usually produced and marketed in crystalline form. However, the phase transformation among riboflavin polymorphs and preparation mechanism of stable crystal form have not been clarified, hindering the production optimization and storage management of products. In this work, the relationship of phase transformation among the riboflavin polymorphs was elucidated, and their thermal stability as well as hygroscopicity were evaluated. Anhydrate I is the most stable form with the best thermal stability and lowest hygroscopicity could not be prepared in antisolvent crystallization process, where monohydrate is the most frequent form. Consequently, a solution-mediated phase transformation (SMPT) process was proposed to prepare anhydrate I from monohydrate. In-situ Raman, UV–VIS spectrum and Powder X-ray Diffraction were utilized to monitoring the SMPT process. It was found that the nucleation and growth of anhydrate I was the rate-determining step. Elevated temperatures, reduced solid loads and addition of seeds can accelerate the conversion procedure. This work provides guiding significance for the product development and quality control of Riboflavin.

Enhanced dissolution of curcumin-resorcinol cocrystal by the inhibition effect of HPMCAS on solution-mediated phase transformation

The present study aimed to investigate the inhibition effect of polymers on the solution-mediated phase transformation (SMPT) of cocrystals during dissolution. Curcumin-resorcinol (CUR-RES) cocrystal was prepared by slow solvent evaporation, and the best precipitation inhibitor of curcumin (CUR) was selected from five polymers including hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC) E5, HPMC E50, Poloxamer 188 (P188) and polyethylene glycol (PEG) 6000 by solvent-shift precipitation test. Then non-sink dissolution tests and intrinsic dissolution rate (IDR) tests were performed with or without HPMCAS to explore the influence of HPMCAS on the dissolution of the cocrystal. It was showed that HPMCAS could effectively inhibit the crystallization of CUR so that the dissolved drug concentration in a predissolved 0.1 % HPMCAS solution at 2 h was nearly 15 μg/mL, which was at least 150 times higher than that without HPMCAS. The red CUR-RES cocrystal turned gradually to yellow CUR during the dissolution tests in the absence of HPMCAS, while the transformation was prevented in the presence of HPMCAS. The present work fully exploits the solubility advantages of CUR-RES cocrystal via the use of precipitation inhibitor and offers important insights into reducing the risk of SMPT during cocrystal dissolution, which is crucial for the development of pharmaceutical cocrystal formulations.

Revealing the mechanism of polymer inhibition of 2,4-dichlorophenoxyacetic acid Polymorphs phase transition by experimental and molecular dynamics simulation

It is well-established that the occurrence of solution-mediated phase transformation makes the precise preparation of pure metastable forms of drugs by solution crystallization methods extremely challenging. This paper demonstrates that the polyvinylpyrrolidone (PVP) and N-vinyl-2-pyrrolidone and vinylacetate (PVPVA) polymers can effectively prevent crystal form transformation of the 2,4-dichlorophenoxyacetic acid (2,4-D) in the solution. We performed the induction time and crystal growth rate experiments at different supersaturation levels. The results showed that the polymer additives can significantly prolong the induction time and have an inhibition effect on crystal nucleation. The PVP and PVPVA almost completely inhibited the crystal growth in both the length and width directions. Molecular dynamics simulations reveal that the interaction energy between the polymer and crystal face determines the magnitude of the inhibition effect on the crystal growth of stable polymorph Form I. These results suggest that polymorph control during the solution crystallization process can be achieved by adding polymer additives.

Polymorphs of a 1:1 salt of sulfadiazine and piperazine–relative stability, dissolution studies, pharmacokinetics and anti-meningitis efficiency

Two new salt forms of sulfadiazine (SDZ) and piperazine (PIP) were synthesized and characterized. Out of the two polymorphs (SDZ-PIP Ⅰ and SDZ-PIP II), SDZ-PIP Ⅱ is the more stable form at low temperature, room temperature and high temperature. The solution-mediated phase transformation result shows that SDZ-PIP II can transform into pure SDZ within 15 s in phosphate buffer at 37 °C, which leads to a loss in solubility advantage. The addition of 2 mg/mL PVP K30, a polymeric crystallization inhibitor, maintains the solubility advantage and permits supersaturation for a longer period of time. SDZ-PIP II showed 2.5 times the solubility of SDZ alone. The area under the curve (AUC) of SDZ-PIP II with 2 mg/mL PVP K30 was approximately 165% of that of SDZ alone. Moreover, SDZ-PIP II with PVP K30 was more effective than SDZ alone in treating meningitis. Therefore, the SDZ-PIP II salt improves the solubility, bioavailability, and anti-meningitis activity of SDZ.

Mechanistic Insight of Polymer Effects on the Kinetic of Solution-Mediated Phase Transformation of Nitrofurantoin Anhydrate to Monohydrate.

Nitrofurantoin is an effective antibacterial drug for the treatment of lower urinary tract infection. However, the anhydrate form can easily transform to the less soluble hydrate form (monohydrate) during dissolution, resulting in a reduction of dissolution rate and oral bioavailability. Therefore, inhibition of phase transformation is vital to stabilize the quality of drugs. In this work, the potential of polyethylene glycol (PEG 8000), polyvinyl pyrrolidone (PVP K30), poloxamer 188 and hydroxypropyl methylcellulose (HPMC) to inhibit the hydration of nitrofurantoin during dissolution was investigated by experimental and simulation approaches. The rates of phase transformation were decreased in the presence of PEG 8000 and poloxamer 188, and PVP K30 and HPMC completely inhibited the phase transformation of anhydrate. The abundant hydrogen bond donor and acceptor groups of PVP and HPMC may easily establish intermolecular interactions with nitrofurantoin molecules, accounting for stronger inhibition of nucleation. Besides, the molecular dynamic simulation further indicated the formation of more extensive interactions between PVP K30 (or HPMC) and the (111) face of monohydrate, suggesting that the strong absorption of polymers on the surface and thus block the sites for incorporation of new growth. This study provides a mechanistic insight into the inhibition of nitrofurantoin hydration by polymeric additives, which helps design formulations and improve the physical stability of anhydrate.

Solid-state characterization of ibuprofen-isonicotinamide cocrystals prepared by electrospraying and solvent evaporation.

Aim: Electrospraying (ELS) was used to prepare micronized ibuprofen-isonicotinamide cocrystal (IBU-INA-ELS) and its properties were compared with the solvent evaporated cocrystal (IBU-INA-SE). Methods: Solid-state characterization of crystalline phase, production yield, particle size, powder flow, wettability, solution mediated phase transformation (SMPT), and dissolution rate were measured. Results: The ELS produced phase pure particles of IBU-INA with a size of 1.46μm and yield of 72.3%. This cocrystal improved the intrinsic dissolution rate and powder dissolution rate of IBU by 3.6- and 1.7-fold, respectively. Our experiments showed that the dissolution of IBU-INA was affected by particle size, solubility, SMPT and wettability. Conclusion: ELS produced micronized cocrystals for improving dissolution of ibuprofen with a high yield in a single step and mild conditions.

Effects of various parameters on solution-mediated phase transformation of calcium d-gluconate: an approach to obtain pure metastable monohydrate.

The high risk of solution-mediated phase transformation (SMPT) from the metastable monohydrate to stable Form I makes it difficult to produce pure metastable monohydrate of calcium d-gluconate. In this work, we explored the effect of various operating parameters on the SMPT of calcium d-gluconate in water and proposed an effective approach to obtain the desired monohydrate. First, the two forms of calcium d-gluconate were characterized and compared using powder X-ray diffraction (PXRD), thermal analysis, and Raman spectroscopy. The lower solubility of Form I in water illustrates its higher thermodynamic stability than monohydrate when the temperature is higher than 292 K. Afterward, the SMPT of calcium d-gluconate from monohydrate to Form I was investigated in water using in situ Raman spectroscopy combined with scanning electron microscopy and PXRD. Results showed that the nucleation and growth of Form I was the rate-limiting step in the SMPT from monohydrate to Form I. The phase transformation from monohydrate to Form I was delayed to produce pure monohydrate by decreasing temperature and agitation rate, reducing the amount of solid loading, and increasing the particle size of solid loading. Furthermore, the transformation kinetics were studied by the JMA model to explore how temperature influences the SMPT process. This study enriches the study of the calcium d-gluconate SMPT mechanism, and also provides guidance for obtaining high-quality injection-grade calcium gluconate monohydrate.

Revealing the role of polymer in the robust preparation of the 2,4-dichlorophenoxyacetic acid metastable crystal form by AI-based image analysis

The selective preparation of pure polymorphs is of great significance in the pharmaceutical industry. This work aims to prepare the pure metastable Form II of the 2,4-dichlorophenoxyacetic acid (2,4-D) and investigate the effects of polymer on the solution-mediated phase transformation (SMPT) with the assistance of AI-based image analysis. Firstly, a convolutional neural network model was built to segment and classify crystal Form II (needle) and crystal Form I (bulk). Then, the polymorphic transition kinetics based on the changes in the area of the two 2,4-D crystal forms over time was precisely and efficiently analyzed. The results revealed that the polymer additives mainly inhibited the dissolution of crystal Form II and the nucleation of crystal Form I, thereby obtaining pure metastable Form II of 2,4-D. The AI-based image analysis of the process evolution strategy offers insightful guidance on the manufacture of pure metastable crystal forms in the pharmaceutical and chemical industry. Metastable needle-like Form II of 2,4-D could be robustly prepared with polymer additive assistance. A convolutional neural network model, Crys-form CNN, was built to visualize and quantify the additives' effects on the crystal transformation process and determine the rate-controlling steps. • Pure metastable of the 2,4-D was robustly prepared with the assistance of polymer. • An AI-based image analysis model, Crys-form CNN, was built. • The SMPT of 2,4-D in the cuvette was in-situ monitored and visualized. • The effects of polymers on the SMPT were quantified by Crys-form CNN.

Inhibiting Sublimation of Thymol by Cocrystallization

A thymol:4,4’-dipyridyl (2:1) cocrystal (Form I) is reported to suppress thymol sublimation. The cocrystal was prepared via solution-mediated phase transformation and its structure is sustained by O-H (phenol) ··· N (pyridyl) hydrogen bonds between two individual components. A cocrystal polymorph (Form II) was formed via solid state transformation or via vapor phase upon heating. Using gravimetry analysis, it was demonstrated that cocrystal Form I decreased the sublimation rate of thymol by 38-fold. This study demonstrates that cocrystallization is an effective approach to reduce vapor pressure and sublimation of solids, thus achieving odor-masking.

Solution Stability of Pharmaceutical Cocrystals

In recent years, pharmaceutical cocrystals as a new solid form have received considerable attention among the applied novel methods for modifying drug substance characteristics. Crystal engineering offers an excellent opportunity to improve physicochemical and pharmacokinetic properties such as solubility, dissolution rate, permeability, bioavailability, biochemical/physical stability, etc. Application of the cocrystal form in the pharmaceutical industry and in academia is becoming a popular method to overcome solubility disadvantages of the active pharmaceutical ingredient (API). Due to manipulation of the API crystalline structure by cocrystal formation, solubility is not the only affected property; some other properties of the newly produced solid form must be considered to fulfill the desired therapeutic efficacy. The stability of the cocrystal in solution is one of these influential features. Regarding the aqueous nature of the gastrointestinal tract, unwanted solution-mediated phase transformation of a cocrystal to a more stable form causes inefficient drug delivery. It may potentially reduce the drug concentration in the circulation. Cocrystal transformation products could be a different polymorph, hydrated form, or mixture of the API and coformer. This review focuses on the solution stability of cocrystals and the effects of various factors such as polymers, surfactants, biorelevant media, organic solvents, and pH.

Investigation of Glycine Polymorphic Transformation by In Situ ATR-FTIR and FT-Raman Spectroscopy

The solution-mediated phase transformation of α-form to γ-form glycine, including dissolution of metastable α-form, nucleation, and growth of stable γ-form during polymorphic transformation, was investigated using in situ attenuated total-reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and Fourier transform Raman spectroscopy (FT-Raman). The mechanistic influence of operating parameters such as agitation speed, crystallization temperature, α-form seed concentration, and NaCl concentration on polymorphic phase transformation was examined. When the agitation speed, crystallization temperature, and NaCl concentration were increased, the polymorphic transformation process was improved due to the promotion of nucleation and growth of stable γ-form, in addition to the promotion of dissolution of metastable α-form. Moreover, the time to induce γ-form nucleation and complete conversion of α-form to γ-form was also reduced with increasing α-form seed concentration.

In situ discrimination of polymorphs and phase transformation of sulfamerazine using quartz crystal microbalance

A novel strategy utilizing the quartz crystal microbalance (QCM) was developed for the in situ discrimination of polymorphic nucleation (form-I and form-II) and phase transformation of sulfamerazine (SMZ) in cooling crystallization. According to Ostwald's rule of stages, metastable form-I of SMZ is first nucleated and then shifted to stable form-II by solution-mediated phase transformation. Through surface modification with the self-assembled monolayer technique of a functional group, QCM distinctively detects the formation of the two polymorphs. The results indicated that –NH2 (among the several functional groups tested) selectively accommodated stable form-II on the QCM sensor's surface and completely prevented the adsorption of metastable form-I on the surface. Therefore, the–NH2-terminated QCM detected the formation of form-I only using the solution viscosity variation on the surface. However, it monitored the nucleation and growth of form-II via the solid mass change on the surface during the phase transformation of form-I to form-II. This strategy suggests a new and precise solution for in situ discrimination of SMZ polymorphs and their phase transformation.

Dissolution Profiles of Carbamazepine Cocrystals with Cis-Trans Isomeric Coformers.

The purpose of the present study was to investigate the dissolution profiles of cocrystals with cis-trans isomeric coformers. Previously, the carbamazepine (CBZ) cocrystals with even-carbon dicarboxylic acids showed higher supersaturation than those with odd-carbon ones, attributed to particle surface solution-mediated phase transformation (PS-SMPT) to CBZ dihydrate (CBZ DH). However, it has been unknown whether this odd-even pattern holds for cis-trans isomeric coformers. CBZ cocrystals with maleic acid (MLE) and fumaric acid (FUM) (CBZ-FUM anhydrate (CBZ-FUM AH) and monohydrate (CBZ-FUM H2O)) were employed as model cocrystals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, and polyethylene glycol 6000 (PEG) were used as precipitation inhibitors. Dissolution tests were performed under a non-sink condition. Residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscope, and scanning electron microscope. All cocrystals showed little supersaturation in the absence of a polymer. In 0.1% HPMC, CBZ-FUM AH showed significant supersaturation, whereas CBZ-MLE and CBZ-FUM H2O did not for the first two hours. HPMC reduced the initial dissolution rate of CBZ-MLE and CBZ-FUM H2O while inducing the highest supersaturation among the polymers after 96h. The particle surface changed from a smooth plane to a striped pattern, but little or no CBZ DH was detected. The cocrystals with cis-trans isomeric coformers showed different dissolution profiles. HPMC increased the dissolution rate of CBZ-FUM AH by inhibiting PS-SMPT but reduced the dissolution rate of CBZ-MLE and CBZ-FUM H2O without inducing PS-SMPT. The striped pattern was suggested to be due to surface etching rather than PS-SMPT.

Impact of bile salt on solution-mediated phase transformation of pharmaceutical cocrystals: The importance of coformer release kinetics

Cocrystal engineering has become increasingly prevalent as an efficient and versatile route to overcome solubility limitations and improve the oral bioavailability of poorly soluble drugs. However, the unwanted solution-mediated phase transformation of cocrystals to less soluble parent drugs in the gastrointestinal tract may fail to deliver the drug in the body in a sufficient quantity. This study explores how bile salt sodium taurocholate (STC) affects the dissolution performance of indomethacin-saccharin (IMC-SAC) cocrystals. Fluorescence microscopy was used for in situ monitoring of the phase transformation of IMC-SAC cocrystals in the presence and absence of STC during dissolution. Intrinsic dissolution tests, atomic force microscopy and energy dispersive X-ray spectroscopy revealed that there was a significant relationship between the coformer release rate and the kinetics of the phase transformation of cocrystals. The addition of low-concentration STC in the buffer significantly inhibited the phase transformation of IMC-SAC cocrystals by retarding the release of SAC from cocrystals, leading to enhanced release rates of IMC. A molecular dynamics simulation revealed that preferential adsorption of STC molecules on the cocrystal surface may be responsible for the suppression of drastic release of SAC from the cocrystal lattice, thus preventing a rapid crystallization of IMC at the solid–liquid interface. The presence of STC in the buffer could also prolong the supersaturation of IMC, accounting for the overall improved in vitro and in vivo performance of IMC-SAC cocrystals. This study provides a deeper insight into the mechanisms of solution-mediated phase transformation of cocrystals in the presence of endogenous surfactant, which could also be used as an effective strategy to improve the absorption performance of pharmaceutical cocrystals by minimizing the risk of phase transformation during dissolution.

Polymeric precipitation inhibitor differently affects cocrystal surface and bulk solution phase transformations

During the dissolution of cocrystal particles, solution-mediated phase transformation (SMPT) can occur either on the particle surface (PS-SMPT) or in the bulk phase solution (BP-SMPT). In this study, we compared the effect of various polymers on PS-SMPT and BP-SMPT for the first time using carbamazepine saccharine cocrystal (CBZ-SAC) as a model drug. Polyethylene glycol 6000 (PEG), polyvinylpyrrolidone K-30 (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), amino methacrylate copolymer (EPO), and methacrylic acid copolymers (L100-55) were used as polymeric precipitation inhibitors. In the non-sink dissolution test, CBZ-SAC rapidly transforms to CBZ dihydrate (CBZ DH) via PS-SMPT in the absence of polymers. The polymers enhanced the dissolution rate and subsequent supersaturated CBZ concentration in the order of HPMC-AS > HPMC > EPO ≫ PVP ≈ L100-55 ≈ PEG. On the other hand, in the solvent-shift precipitation test, these polymers inhibited the precipitation of CBZ DH in a different order (EPO > HPMC > HPMC-AS ≫ L100-55 ≈ PVP ≫ PEG). The polymers affected the crystal habit of CBZ DH differently between PS-SMPT and BP-SMPT. Direct PS-SMPT observation by real-time polarized light microscopy (RT-PLM) showed that PS-SMPT was significantly inhibited by HPMC-AS, HPMC, and EPO, but less by PVP, L100-55, and PEG. Differences in solid surface pH and heterogeneous nucleation were discussed as the reason for the difference in the inhibitory effect between polymers in PS-SMPT and BP-SMPT. In conclusion, the inhibitory effect of polymers can differ between PS-SMPT and BP-SMPT. For the successful development of a cocrystal formulation, it is important to select a potent inhibitor of PS-SMPT.

Solution-Mediated Phase Transformation on Crystal Facets of Carbamazepine–Saccharin Cocrystals

The purpose of the present study was to investigate the effect of crystal facets on solution-mediated phase transformation (SMPT) at cocrystal surfaces during dissolution in aqueous media. Previous...

Effect of Surfactants and Polymers on the Dissolution Behavior of Supersaturable Tecovirimat-4-Hydroxybenzoic Acid Cocrystals.

(1) Background: Pharmaceutical cocrystals have attracted remarkable interest and have been successfully used to enhance the absorption of poorly water-soluble drugs. However, supersaturable cocrystals are sometimes thermodynamically unstable, and the solubility advantages present a risk of precipitation because of the solution-mediated phase transformation (SMPT). Additives such as surfactants and polymers could sustain the supersaturation state successfully, but the effect needs insightful understanding. The aim of the present study was to investigate the roles of surfactants and polymers in the dissolution-supersaturation-precipitation (DSP) behavior of cocrystals. (2) Methods: Five surfactants (SDS, Poloxamer 188, Poloxamer 407, Cremophor RH 40, polysorbate 80) and five polymers (PVP K30, PVPVA 64, HPC, HPMC E5, CMC-Na) were selected as additives. Tecovirimat-4-hydroxybenzoic (TEC-HBA) cocrystals were chosen as a model cocrystal. The TEC-HBA cocrystals were first designed and verified by PXRD, DSC, SEM, and FTIR. The effects of surfactants and polymers on the solubility and dissolution of TEC-HBA cocrystals under sink and nonsink conditions were then investigated. (3) Results: Both the surfactants and polymers showed significant dissolution enhancement effects, and most of the polymers were more effective than the surfactants, according to the longer Tmax and higher Cmax. These results demonstrate that the dissolution behavior of cocrystals might be achieved by the maintained supersaturation effect of the additives. Interestingly, we found a linear relationship between the solubility and Cmax of the dissolution curve for surfactants, while no similar phenomena were found in solutions with polymer. (4) Conclusions: The present study provides a basis for additive selection and a framework for understanding the behavior of supersaturable cocrystals in solution.

Tailoring Release Profiles of BCS Class II Drugs Using Controlled Release Amorphous Solid Dispersion Beads with Membrane-Reservoir Design: Effect of Pore Former and Coating Levels.

Poor aqueous solubility is a major limiting factor during the development of BCS Class II drug candidates in a solid oral dosage form. Conventional amorphous solid dispersion (ASD) systems focus on maximizing the rate and extent of release by employing water-soluble polymeric crystallization inhibitors; however, they often encounter rapid supersaturation and solution-mediated phase transformation (SMPT). Therefore, in this work, a controlled release membrane was introduced onto ASD beads to mitigate the SMPT problem. A membrane-reservoir controlled release amorphous solid dispersion (CRASD) bead system was designed, and the effects of the coating thickness and pore former content on drug release profiles were investigated. CRASD beads were manufactured by spray-coating polyvinyl acetate with polyvinylpyrollidone (PVP) as a pore former onto sugar bead substrates layered with the ASD reservoir of celecoxib and PVP. Raising the pore former content and/or lowering the coating level imparted higher release rates and supersaturation levels. The extent of release, measured by the area under the curve, was greatest when an optimal balance between the release rate and peak concentration could be established, corresponding to a high pore former/high coating level combination. Attributed to a thicker membrane structure with a higher pore former, rapid initial release could be achieved, yet controlled gradually for several hours, avoiding the critical threshold where the onset of SMPT predominates. The greater membrane capacity to transiently immobilize drug molecules (i.e., preserve amorphicity) and gradually release drug over a prolonged duration may be key to balancing supersaturation on both sides of the membrane; hence coating variables should be tactfully selected to exploit this benefit.

Tailoring crystallization and physical properties of palm mid-fraction with sorbitan tristearate and sucrose stearate

This paper addresses sorbitan and sucrose ester in physical transformations of palm mid-fraction (PMF). Both emulsifiers influenced the crystallization properties of PMF, mainly due to emulsifier solubility, which affects its ability to interfere with the kinetics of solution-mediated phase transformations. DSC results corroborate the polymorphism analysis, indicating that the mechanism and rate of phase transformation depend on the chemical structure and amount of each emulsifier. The addition of sorbitan tristearate (STS) and sucrose stearate (S-370) increased the crystallization speed of the PMF and caused changes in the crystallization behavior. STS favored the β'→β transition, while S-370 stabilized the β'-form. We can conclude that the presence of emulsifiers dissimilar to the composition of PMF modified its physical structure, either by increasing the liquid fraction or by reducing molecular motion, facilitating or preventing polymorphic transformations.