In Vitro Simulation of the Fasted Gastric Conditions and Their Variability to Elucidate Contrasting Properties of the Marketed Dabigatran Etexilate Pellet-Filled Capsules and Loose Pellets.

Variability of the gastrointestinal tract is rarely reflected in in vitro test protocols but often turns out to be crucial for the oral dosage form performance. In this study, we present a generation method of dissolution profiles accounting for the variability of fasted gastric conditions. The workflow featured 20 biopredictive tests within the physiological variability. The experimental array was constructed with the use of the design of experiments, based on three parameters: gastric pH and timings of the intragastric stress event and gastric emptying. Then, the resulting dissolution profiles served as a training data set for the dissolution process modeling with the machine learning algorithms. This allowed us to generate individual dissolution profiles under a customizable gastric pH and motility patterns. For the first time ever, we used the method to successfully elucidate dissolution properties of two dosage forms: pellet-filled capsules and bare pellets of the marketed dabigatran etexilate product Pradaxa. We showed that the dissolution of capsules was triggered by mechanical stresses and thus was characterized by higher variability and a longer dissolution onset than observed for pellets. Hence, we proved the applicability of the method for the in vitro and in silico characterization of immediate-release dosage forms and, potentially, for the improvement of in vitro-in vivo extrapolation.

An extension of biorelevant fed-state dissolution tests to clinical pharmacokinetics - A study on gastrointestinal factors influencing rivaroxaban exposure and efficacy in atrial fibrillation patients.

A direct oral anticoagulant rivaroxaban fails to prevent stroke and systemic embolism in one-to-several percent of patients with nonvalvular atrial fibrillation (NVAF), but the reasons are unknown. The study used semi-mechanistic in vitro-in vivo prediction (IVIVP) modeling to explore the reasons for ineffective thrombosis prevention in NVAF patients. Steady-state drug concentrations in plasma were measured at 0 h (Ctrough), 3 h (C3h), and 12 h post-dosing in thirty-four patients treated with 20 mg rivaroxaban daily. The clinical data were compared against "virtual twins" generated with a novel IVIVP model that combined drug dissolution modeling, mechanistic description of gastric drug transit, and population pharmacokinetics defining the variability of drug disposition. The nonresponders had significantly lower C3h and Ctrough than the responders (p < 0.001) and the covariates included in the population pharmacokinetic submodel did not fully explain this difference. Simulations involving varied gastrointestinal parameters in the "virtual twins" revealed that lower small intestinal effective permeability (Peff), rather than a slower stomach emptying rate, could explain low rivaroxaban exposure in the nonresponders. IVIVP modeling was effectively used for exploring pharmacotherapy failure. Low Peff, found as a major determinant of ineffective rivaroxaban treatment, encourages further research to find (pato)physiological factors influencing suboptimal absorption.

Effect of Compaction Pressure on the Enzymatic Activity of Pancreatin in Directly Compressible Formulations.

Tableting of biomolecules is a challenging formulation phase due to their sensitivity to various process parameters, such as compression pressure, process dynamics, or the temperature generated. In the present study, pancreatin was employed as a model enzyme mixture, which was formulated in tablet form utilizing the synergistic effects of brittle and plastic excipients (dibasic calcium phosphate and microcrystalline cellulose, respectively). The effect of varying compaction pressure and lubricant concentration on the generated temperature and enzymatic activity was evaluated. The tablets were analyzed for pancreatin content and the activity of two enzymes (protease and amylase) using pharmacopoeial tests. This study indicated that the formulations proposed here allow tableting over a wide range of compaction pressures without adversely affecting pancreatin content and its enzymatic activity.

A Rational Approach to Predicting Immediate Release Formulation Behavior in Multiple Gastric Motility Patterns: A Combination of a Biorelevant Apparatus, Design of Experiments, and Machine Learning.

Gastric mechanical stress often impacts drug dissolution from solid oral dosage forms, but in vitro experiments cannot recreate the substantial variability of gastric motility in a reasonable time. This study, for the first time, combines a novel dissolution apparatus with the design of experiments (DoE) and machine learning (ML) to overcome this obstacle. The workflow involves the testing of soft gelatin capsules in a set of fasted-state biorelevant dissolution experiments created with DoE. The dissolution results are used by an ML algorithm to build the classification model of the capsule's opening in response to intragastric stress (IS) within the physiological space of timing and magnitude. Next, a random forest algorithm is used to model the further drug dissolution. The predictive power of the two ML models is verified with independent dissolution tests, and they outperform a polynomial-based DoE model. Moreover, the developed tool reasonably simulates over 50 dissolution profiles under varying IS conditions. Hence, we prove that our method can be utilized for the simulation of dissolution profiles related to the multiplicity of individual gastric motility patterns. In perspective, the developed workflow can improve virtual bioequivalence trials and the patient-centric development of immediate-release oral dosage forms.

The Use of Calcium Phosphate-Based Starter Pellets for the Preparation of Sprinkle IR MUPS Formulation of Rosuvastatin Calcium.

Sprinkle formulations represent an interesting concept of medicinal products aimed at the steadily growing population of patients suffering from swallowing difficulties (dysphagia). In the present work, immediate-release sprinkle MUPS (multiple-unit pellet system) containing rosuvastatin calcium as a model drug substance was successfully developed. The formulation was prepared by drug layering technique using novel calcium phosphate-based starting pellets (PharSQ® Spheres CM) of three different particle sizes. The study showed that the developed multiparticulates were characterized by uniform distribution of coating layers thickness, as well as fast dissolution rate (more than 85% of rosuvastatin calcium dissolved within 30 min, as required by the relevant USP/NF monograph). Rosuvastatin calcium, like other statins, has a bitter, unpleasant taste. Investigations conducted with an electronic tongue suggested that the developed formulation achieved the desired taste-masking efficiency. The effect was found to be particle size-dependent, improving as the size of the multiparticulates increased.

Application of a novel PhysioCell apparatus for biopredictive dissolution tests of oral immediate release formulations - A case study workflow for in vitro-in vivo predictions.

Biorelevant dissolution tests of oral solid dosage forms open the gate to valid in vitro-in vivo predictions (IVIVP). A recently developed apparatus, PhysioCell, allows mimicking the fluid flow and pressure waves occurring in the human fasted stomach. In this work, we used the PhysioCell to perform IVIVP for vortioxetine immediate-release (IR) tablets: the originator (Brintellix) and generic product candidates (VORTIO). The dissolved drug was monitored in the gastric (StressCell) and intestinal (Collection Vessel) compartments that contained biorelevant media. Simulated intermittent gastric stress at 15 min and "housekeeping wave" at 30 min increased the dissolution of Brintellix formulations only. A mechanistic model that best described the observations involved the first-order tablet disintegration with a stress-induced enhancement for Brintellix, dissolution of solid particles in the StressCell, and drug transfer to the Collection Vessel. Then, a semi-mechanistic pharmacokinetic model with dissolution parameters as inputs simulated vortioxetine plasma concentrations in healthy volunteers after single and multiple dosing of Brintellix. Despite different dissolution characteristics, VORTIO provided similar concentration profiles to the originator. In conclusion, PhysioCell dissolution tests, combined with semi-mechanistic IVIVP, can be successfully used to develop IR dosage forms exhibiting gastric stress-related effects.

Conjunction of semi-mechanistic in vitro-in vivo modeling and population pharmacokinetics as a tool for virtual bioequivalence analysis - a case study for a BCS class II drug.

Virtual bioequivalence trial (VBE) simulations based on (semi)mechanistic in vitro-in vivo (IVIV) modeling have gained a huge interest in the pharmaceutical industry. Sophisticated commercially available software allows modeling variable drug fates in the gastrointestinal tract (GIT). Surprisingly, the between-subject and inter-occasion variability (IOV) of the distribution volumes and clearances are ignored or simplified, despite substantially contributing to varied plasma drug concentrations. The paper describes a novel approach for IVIV-based VBE by using population pharmacokinetics (popPK). The data from two bioequivalence trials with a poorly soluble BCS class II drug were analyzed retrospectively. In the first trial, the test drug product (biobatch 1) did not meet the bioequivalence criteria, but after a reformulation, the second trial succeeded (biobatch 2). The popPK model was developed in the Monolix software (Lixoft SAS, Simulation Plus) based on the originator's plasma concentrations. The modified Noyes-Whitney model was fitted to the results of discriminative biorelevant dissolution tests of the two biobatches and seven other reformulations. Then, the IVIV model was constructed by joining the popPK model with fixed drug disposition parameters, the drug dissolution model, and mechanistic approximation of the GIT transit. It was used to simulate the drug concentrations at different IOV levels of the primary pharmacokinetic parameters and perform the VBE. Estimated VBE success rates for both biobatches well reflected the outcomes of the bioequivalence trials. The predicted 90% confidence intervals for the area under the time-concentration curves were comparable with the observed values, and the 10% IOV allowed the closest approximation to the clinical results. Simulations confirmed that a significantly lower maximum drug concentration for biobatch 1 was responsible for the first clinical trial's failure. In conclusion, the proposed workflow might aid formulation screening in generic drug development.

PhysioCell®; - a Novel, Bio-relevant Dissolution Apparatus: Hydrodynamic Conditions and Factors Influencing the Dissolution Dynamics.

The physiologically relevant dissolution apparatuses simulate various aspects of gastrointestinal physiology and help to understand and predict the in vivo behavior of an oral dosage form. In this paper, we present and characterize for the first time a novel bio-relevant dissolution apparatus - PhysioCell®;. We evaluated the impact of several factors on the hydrodynamic conditions in the key vessel of the apparatus - the StressCell. We observed that the medium flow rate, but not the glass beads' size or amount, significantly influenced the dissolution rate. The relationship was disproportional: the increase in the flow rate from 4.6 to 9.0 mL/min reduced the dissolution time of 85% (T85) of the NaCl tablet by 46%, but from 134 to 300 mL/min decreased the T85 only by 24%. At the same time, the contractions of the StressCell's elastic walls promoted the content mixing and enhanced the dissolution rate of the paracetamol tablets: even very rare mixing contractions (1 per 10 min) decreased the T85 over twofold for the flow rate of 8 mL/min. In conclusion, the hydrodynamic conditions in the StressCell affect the dissolution of solid dosage forms and the understanding of these effects is crucial for modeling physiologically-based test conditions in the novel apparatus. Combinations of the unique PhysioCell®;features - adjustable medium flow, temperature control, controllable pH gradients and predefined mechanical agitation - can create a set of dissolution test scenarios for characterization of oral dosage forms and, in the future, making the in vitro-in vivo predictions. Graphical Abstract.

Dissolution of a Biopharmaceutics Classification System Class II Free Acid from Immediate Release Tablets Containing a Microenvironmental pH Modulator: Comparison of a Biorelevant Bicarbonate Buffering System with Phosphate Buffers.

Poor water dissolution of active pharmaceutical ingredients (API) limits the rate of absorption from the gastrointestinal tract. Increasing the pH of a solid form microenvironment can enhance the dissolution of weakly acidic drugs, but data on this phenomenon in a physiologically relevant bicarbonate media are lacking. In this paper, we examined the effect of a microenvironmental pH modulator (Na2HPO4) on the dissolution of a Biopharmaceutics Classification System (BCS) class II free weak acid (ibuprofen) at biorelevant conditions, including an automatic bicarbonate buffering system, as well as in compendial (50 mM) and low-concentration (10 mM) phosphate buffers with no external pH control. The tablets of 200 mg ibuprofen with either Na2HPO4 (phosphate formulation, PF) or NaCl (reference formulation, RF) were manufactured using a compression method. In a pH 2 simulated gastric fluid, only PF produced a transient supersaturation of ibuprofen, dissolving a fourfold higher drug amount than RF. In a bicarbonate-buffered simulated intestinal fluid with a dynamically controlled pH (5.7, 7.2, and 5.8 to 7.7 gradient), PF dissolved more drug within 30 min than RF (p ≤ 0.019). Of note, the use of a 50 mM phosphate buffer pH 7.2 provided opposite results-RF dissolved the API much faster than PF. Moreover, 10 mM phosphate buffers of pH 5.6 and 7.2 could neither maintain a constant pH nor mimic the bicarbonate buffer performance. In conclusion, the use of a bicarbonate-buffered intestinal fluid, instead of phosphate buffers, may be essential in dissolution tests of BCS class II drugs combined with pH modulators.

Directly compressible formulation of immediate release rosuvastatin calcium tablets stabilized with tribasic calcium phosphate.

Reliable and stable tablet formulations for rosuvastatin calcium (RSC) in four strengths: 5 mg, 10 mg, 20 mg, and 40 mg have been developed. Rosuvastatin is a cholesterol-lowering statin drug and is known to be unstable during storage. The possibility of its stabilization with inorganic salts of multivalent metals has already been reported in the literature. In the present study, a special grade of tribasic calcium phosphate excipient was used to chemically stabilize RSC in a directly compressible immediate release tablet formulation. The developed tablets exhibited good mechanical properties (breaking force ranging from 177 N to 250 N depending on tablet strength), rapid disintegration (less than three minutes) and fast dissolution rate (85% of the drug substance dissolved within 15 minutes) as well as satisfactory chemical stability during storage under stress conditions (50 °C/80% RH), even compared to the reference commercial product.

The Effects of Various Food Products on Bisphosphonate's Availability.

The bioavailability of orally administered bisphosphonates is very low (<1%) due to their short absorption window in the proximal duodenum and high affinity for food. Food ingredients are able to bind the drug, but the presence of food extends the residence time of bisphosphonates in the absorption window. Therefore, the main goal of this study is to select a group of food products that are characterized by low binding affinity to bisphosphonates and thus will not reduce their availability upon concomitant administration. For this purpose, a combination of three methods was applied: (1) evaluation of sorption capacity for rows of digested food samples in a simulated intestinal environment; (2) evaluation of drug availability in simulated chyme; and (3) evaluation of drug availability using a simulating needle device. The results indicate that food products such as egg white and white bread are most suitable for consumption during oral bisphosphonate intake.

Integration of advanced methods and models to study drug absorption and related processes: An UNGAP perspective.

This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.

Development and Bio-Predictive Evaluation of Biopharmaceutical Properties of Sustained-Release Tablets with a Novel GPR40 Agonist for a First-in-Human Clinical Trial.

Sustained-release (SR) formulations may appear advantageous in first-in-human (FIH) study of innovative medicines. The newly developed SR matrix tablets require prolonged maintenance of API concentration in plasma and should be reliably assessed for the risk of uncontrolled release of the drug. In the present study, we describe the development of a robust SR matrix tablet with a novel G-protein-coupled receptor 40 (GPR40) agonist for first-in-human studies and introduce a general workflow for the successful development of SR formulations for innovative APIs. The hydrophilic matrix tablets containing the labeled API dose of 5, 30, or 120 mg were evaluated with several methods: standard USP II dissolution, bio-predictive dissolution tests, and the texture and matrix formation analysis. The standard dissolution tests allowed preselection of the prototypes with the targeted dissolution rate, while the subsequent studies in physiologically relevant conditions revealed unwanted and potentially harmful effects, such as dose dumping under an increased mechanical agitation. The developed formulations were exceptionally robust toward the mechanical and physicochemical conditions of the bio-predictive tests and assured a comparable drug delivery rate regardless of the prandial state and dose labeled. In conclusion, the introduced development strategy, when implemented into the development cycle of SR formulations with innovative APIs, may allow not only to reduce the risk of formulation-related failure of phase I clinical trial but also effectively and timely provide safe and reliable medicines for patients in the trial and their further therapy.

Development of a Biphasic-Release Multiple-Unit Pellet System with Diclofenac Sodium Using Novel Calcium Phosphate-Based Starter Pellets.

Novel calcium phosphate-based starter pellets were used to develop a biphasic-release multiple-unit pellet system (MUPS) with diclofenac sodium as a model drug in the form of hard gelatin capsules. For comparative purposes, corresponding formulations based on the inert cores made of microcrystalline cellulose, sucrose and isomalt were prepared. The developed system consisted of two types of drug-layered pellets attaining different release patterns: delayed-release (enteric-coated) and extended-release. Dissolution characteristics were examined using both compendial and biorelevant methods, which reflected fed and fasting conditions. The results were collated with an equivalent commercial product but prepared with the direct pelletization technique.

Physiologically Based Dissolution Testing in a Drug Development Process-a Case Study of a Successful Application in a Bioequivalence Study of Trazodone ER Formulations Under Fed Conditions.

Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [µg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [µg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [µg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.

A novel open source tool for ELISA result analysis.

ELISA has become a standard analytical tool in the numerous branches of science and industry. Processing of the ELISA results may be a multistep process, often requiring a prior adaptation, using proprietary software, or exporting the results into external internet platforms. It may be problematic in the light of good documentation practices and maintaining good data integrity. In this paper, we present the development and application of the ELISA Tool software. The program is based on a Python scripting programming language and is available under an open-source license. The ELISA Tool allows users to fully control and validate the calculation procedure through a user-friendly graphical user interface. The modular architecture of the software allows its application in other information technology (IT) projects used for data processing in research laboratories. We successfully applied the ELISA Tool for the analysis of real-life samples. The ELISA Tool allowed import of the measurement data, an approximation of the calibration curves with two different algorithms, exploration and diagnostics of the model fit, and generation of the final report with the calculations while maintaining the raw data file unchanged. We report here for the first time the implementation of the idea of full control over data processing, from measured raw data to the final report. We obtained a transparent, open, registered system of data processing control, independent of third parties. The modular and flexible architecture of the created software encourages its further development following the individual demands of the users.

Biorelevant In Vitro Release Testing and In Vivo Study of Extended-Release Niacin Hydrophilic Matrix Tablets.

Niacin (nicotinic acid, NA) is administered orally as an antihyperlipidemic agent in extended-release (ER) tablets in high doses. Due to rapid absorption and extensive metabolism (non-linear pharmacokinetics), the drug plasma levels are highly variable, which may correlate with side effects. Interestingly, this erratic drug delivery behavior of niacin ER products cannot be clarified by compendial in vitro release testing. The standard dissolution tests do not allow to mimic the selected GI tract characteristics in order to estimate the robustness of formulation under the variability of the physiological conditions. These are characterized by the pH value, impact of motility forces and composition, as well as volume of GI liquids. Our paper demonstrates a comparison of a newly developed ER HPMC niacin formulation with an originator product. The research aimed to design a robust matrix tablet of comparable biopharmaceutical behavior, safety and efficacy. The extensive in vitro investigation, including dynamic studies in flow-through cell apparatus and stress test device, forms the basis for the evaluation of nicotinic acid plasma concentrations in vivo. The occurrence of erratic, multiple NA plasma peaks after the administration of both extended-release products is a result of its local input excess over the metabolic threshold (at the level corresponding to maximum 2% of the administered dose, i.e., 20 mg of drug) due to the mechanical stresses of physiological intensity. We demonstrate how this behavior is similar for both marketed and test products. In this context, we describe how a robust ER matrix and well-designed formulation does not guarantee the test product's bioequivalence to the comparator one out of reasons unrelated to technology and biopharmaceutical properties, but because of the active compound's intrinsic pharmacokinetic characteristics, i.e., highly variable, extensive metabolism of nicotinic acid.

Pressure-assisted solvent- and catalyst-free production of well-defined poly(1-vinyl-2-pyrrolidone) for biomedical applications.

In this work, we developed a fast, highly efficient, and environmentally friendly catalytic system for classical free-radical polymerization (FRP) utilizing a high-pressure (HP) approach. The application of HP for thermally-induced, bulk FRP of 1-vinyl-2-pyrrolidone (VP) allowed to eliminate the current limitation of ambient-pressure polymerization of 'less-activated' monomer (LAM), characterized by the lack of temporal control yielding polymers of unacceptably large disperisites and poor result reproducibility. By a simple manipulation of thermodynamic conditions (p = 125-500 MPa, T = 323-333 K) and reaction composition (two-component system: monomer and low content of thermoinitiator) well-defined poly(1-vinyl-2-pyrrolidone)s (PVP) in a wide range of molecular weights and low/moderate dispersities (M n = 16.2-280.5 kg mol-1, D = 1.27-1.45) have been produced. We have found that HP can act as an 'external' controlling factor that warrants the first-order polymerization kinetics for classical FRP, something that was possible so far only for reversible deactivation radical polymerization (RDRP) systems. Importantly, our synthetic strategy adopted for VP FRP enabled us to obtain polymers of very high M n in a very short time-frame (0.5 h). It has also been confirmed that VP bulk polymerization yields polymers with significantly lower glass transition temperatures (T g) and different solubility properties in comparison to macromolecules obtained during the solvent-assisted reaction.

Phase Diagrams of Polymer-Dispersed Liquid Crystal Systems of Itraconazole/Component Immiscibility Induced by Molecular Anisotropy.

Liquid crystalline (LC) materials and their nonmedical applications have been known for decades, especially in the production of displays; however, the pharmaceutical implications of the LC state are inadequately appreciated, and the misunderstanding of experimental data is leading to possible errors, especially in relation to the physical stability of medicines. The aim of this work was to study LC phases of itraconazole (ITZ), an azole antifungal active molecule, and for the first time, to generate full thermodynamic phase diagrams for ITZ/polymer systems, taking into account isotropic and anisotropic phases that this drug can form. It was found that supercooled ITZ does not form an amorphous but a vitrified smectic (vSm) phase with a glass transition temperature of 59.35 °C (determined using a 10 °C/min heating rate), as is evident from X-ray diffraction and thermomicroscopic (PLM) experiments. Two endothermic LC events with the onset temperature values for a smectic to nematic transition of 73.2 ± 0.4 °C and a nematic to isotropic transformation at 90.4 ± 0.35 °C and enthalpies of transition of 416 ± 34 J/mol and 842 ± 10 J/mol, respectively, were recorded. For the binary supercooled mixtures, PLM and differential scanning calorimetry showed a phase separation with birefringent vSm persistent over a wide polymer range, as noticed especially for the hypromellose acetate succinate (HAS) systems. Both, smectic and nematic, phases were detected for the supercooled ITZ/HAS and ITZ/methacrylic acid-ethyl acrylate copolymer (EUD) mixtures, while geometric restrictions inhibited the smectic formation in the ITZ/poly(acrylic acid) (CAR) systems. The Flory-Huggins lattice theory coupled with the Maier-Saupe-McMillan approach to model anisotropic ordering of molecules was successfully utilized to create phase diagrams for all ITZ/polymer mixtures. It was concluded that in a supercooled ITR/polymer mix, if ITZ is present in a LC phase, immiscibility as a result of molecule anisotropy is afforded. This study shows that the LC nature of ITZ cannot be disregarded when designing stable formulations containing this molecule.