Crystal Polymorphism Research Articles

Selective formation of crystal polymorphs in Er3+-doped Bi2O3 thin films and their photoluminescence properties

The process conditions for selectively forming crystal polymorphs in Er3+-doped Bi2O3 films deposited on Si, SiO2, and C-plane sapphire substrates were systematically investigated. Bi2O3:Er films were deposited at either room temperature or 300 °C and subsequently post annealed to promote crystallization. The critical factor controlling the crystal polymorphs was Er content. When the Er content was less than 1.5 at.%, only α-Bi2O3 phase nucleated upon post annealing. Deposition at 300 °C somewhat lowered the oxidization state, under which β-Bi2O3 structure appeared at lower temperatures and α-Bi2O3 structure appeared at higher temperatures. When the films were doped with over 2 at.% Er3+ ions, the excess Er2O3 stabilized the δ-Bi2O3 structure as the lowest temperature phase. The universal phase transition scheme with increasing annealing temperature was δ-Bi2O3 → β-Bi2O3 → α-Bi2O3. The δ → β transition proceeded through splitting each diffraction peak of δ-Bi2O3 into two components of β-Bi2O3, indicating a correlation between the structures of β-Bi2O3 and δ-Bi2O3. The γ-Bi2O3 phase appeared only in films on Si(100) substrates and after vacuum annealing, suggesting the formation of sillenite (Bi12SiO20). Deposition on C-plane sapphire by using H2O as the oxygen source gas produced a highly (111)-oriented δ-Bi2O3 structure, whereas deposition with O2 yielded a randomly oriented δ-Bi2O3 structure. At Er content exceeding 4 at.%, δ-Bi2O3 was the primary phase in the films on SiO2. The photoluminescence (PL) activity of dopant Er3+ under excitation at a wavelength of 532 nm strongly depended on the crystal polymorphs. α-Bi2O3:Er exhibited intense and stable PL spectra consisting of eight Stark splitting lines. PL from γ-Bi2O3:Er exhibited much weaker two emission lines. δ-Bi2O3:Er and β-Bi2O3:Er films were not emission-active at all. However, δ-Bi2O3:Er film on SiO2 with an Er content of 4 at.% exhibited an intense and broad emission at 1530 and 1560 nm.

Unsupervised Pharmaceutical Polymorph Identification and Multicomponent Particle Mapping of ToF-SIMS Data by Non-Negative Matrix Factorization.

Crystal polymorphism of pharmaceutical compounds directly impacts resulting physicochemical characteristics, a critical aspect in active pharmaceutical ingredient (API) production. Tools to characterize and chemically map these polymorphs at the single particle scale remain important to advancing directed manufacture of targeted polymorphs. Here, time-of-flight secondary ion mass spectrometry (ToF-SIMS) was employed for chemically imaging inkjet printed acetaminophen samples. ToF-SIMS generates large data sets of high spatial resolution images. Extracting relevant data and peaks of interest can be laborious for, and biased by, users. Advances in machine learning approaches have introduced many supervised and unsupervised methods for data analysis. In this study, we apply non-negative matrix factorization (NMF) for the unsupervised analysis of ToF-SIMS chemical image data. More specifically, an expanded variant of NMF, NMFk, was employed to determine the data set's latent dimensionality. NMFk combines the spectral unmixing of traditional NMF with k-means clustering of the resulting factors and an optimization of the reconstruction and clustering. The method was used to identify the number of polymorph phases-and their representative mass spectra-generated from inkjet printed acetaminophen samples. Amorphous, crystalline form I, and crystalline form II polymorphs were observed. The learned polymorph mass spectra were then used to map the learned polymorphs onto subsequent particle samples of acetaminophen. Finally, NMFk also enabled the decomposition of mixed particle samples (i.e., migraine medicine), learning the number of compounds and their composition. The extracted constituent phase mass spectra-representing single compounds-were searched against mass spectral libraries for identification.

Polymorphic Crystallization Behavior of a Poly(butylene adipate) Midblock within a Poly(L-lactide-butylene adipate-L-lactide) Triblock Copolymer.

New biodegradable aliphatic PLLA-PBA-PLLA copolymers with soft poly(butylene adipate) (PBA) and hard poly(l-lactide) (PLLA) building blocks were synthesized via ring-opening polymerization (ROP). Proton nuclear magnetic resonance (1HNMR) was utilized to confirm the volume fraction of PBA (fPBA) within PLLA-PBA-PLLA. It was found that a PBA midblock (PBA-mid) within PLLA-PBA-PLLA-s (PLLA-PBA-PLLA triblock copolymer with a short PLLA block length) might display lamellar domain structure. However, PBA-mid within PLLA-PBA-PLLA-l (PLLA-PBA-PLLA triblock copolymer with a long PLLA block length) might locate itself as a nanoscale cylindrical domain surrounded by a PLLA continuous phase. Polymorphic crystals of PBA-mid within the PLLA-PBA-PLLA copolymers were formed after melt crystallization at the given temperatures, which were studied by differential scanning calorimetry (DSC) and wide-angle X-ray diffraction (WAXD) analysis. According to the WAXD and DSC analyses, it was interesting to find that the α-type crystal of PBA-mid was favorable to develop in the lower temperature region regardless of the state (crystallization or amorphous) of the PLLA component. Additionally, when the PLLA component was held in its amorphous state, it was easier for PBA-mid within the PLLA-PBA-PLLA copolymers to transform from the metastable β-form crystal to the stable α-form crystal. Furthermore, polarized optical microscopy (POM) photos provided direct evidence of the polymorphic crystals of PBA-mid within PLLA-PBA-PLLAs.

Controlled crystallization of metastable polymorphic pharmaceutical: Comparative study of batchwise and continuous tubular crystallizers

The deliberate and reproducible crystallization of metastable polymorphs of active pharmaceutical ingredients (APIs) from solution remains difficult and is still far from trivial. The main challenge is to prevent cross nucleation of the stable form. The traditional cooling experiments in a batch crystallizer cannot repeatably produce aripiprazole (APZ) metastable Form III within selected initial concentrations and cooling rates. The computational fluid dynamics simulations confirmed that fluctuations in temperature and solution concentration in the batch crystallizer would induce the nucleation of stable crystal forms and accelerate solvent-mediated phase transformation. This work presents, for the first time, ultrasonic- and slug-assisted tubular crystallizers for the continuous and controllable preparation of pure metastable crystal Form III of APZ. The ultrasound-assisted air segmented plug flow tubular crystallizer provides an efficient configuration to produce high purity metastable polymorphism pharmaceuticals, which also offers a facile approach for the continuous manufacturing of drug substances.

Stereocomplexed Materials of Chiral Polymers Tuned by Crystallization: A Case Study on Poly(lactic acid)

ConspectusWidespread in chemistry and biochemistry, chirality strongly affects the biological, chemical, material, and physical properties. As a downstream derivative, the enantiopure polymers of opposite chirality can cocrystallize in the stereocomplex (SC) in their enantiomeric blends or block copolymers, which endows the materials with improved physical properties and specific functions such as enhanced melting temperature, thermal stability, crystallizability, and hydrolytic resistance. A well-studied stereocomplexable polymer is poly(lactic acid) (PLA); both of its two enantiomers, poly(l-lactic acid) and poly(d-lactic acid), are biobased and biodegradable. SC crystallization is a simple and practical approach to improve the essential properties and functions of chiral polymers, which advances existing polymer applications and paves a new way to develop a variety of novel materials. However, it is noteworthy that not all of the enantiomeric blends of l- and d-polymers can exclusively crystallize into SC crystals in a typical crystallization process, which is usually accompanied by the homocrystallization of each individual enantiomer. Developing stereocomplexed materials with controlled crystalline structure, physical properties, and functions is still challenging. Consequently, studying and discussing the stereocomplexed materials developed by harnessing SC crystallization are of fundamental importance not only to obtain novel functional materials but also to promote the advancement of material researches.In this Account, we concisely summarize and analyze our recent progresses in SC crystallization and stereocomplexed materials of PLA, which initializes a conceptual methodology to study and develop the stereocomplexed materials from chiral polymers. We first introduce various approaches for controlling the polymorphic crystallization structure, in order to promote the SC crystallization of high-molecular-weight PLA and to prepare the stereocomplexed materials. Then, we present our efforts on the preparation of novel stereocomplexed materials such as micelles, physical hydrogels, and elastomers by harnessing SC crystallization. These stereocomplexed materials show good physical properties (e.g., thermomechanical property and thermal resistance) and can further be functionalized toward shape memory, drug release, and thermoresponsive materials. These works have established a practical platform to unveil the relationships between crystalline structure, physical properties, and functions of stereocomplexed materials. At the end of the Account, we offer a brief summary and outlooks in this field. Even though a case study on PLA is focused in this Account, a similar methodology can be generalizable to other chiral polymer systems. We hope that this Account will evoke new inspirations and innovative work in the field of stereocomplexed materials of chiral polymers in the near future.

Correcting π-delocalisation errors in conformational energies using density-corrected DFT, with application to crystal polymorphs

We consider several molecules characterised by π-electron conjugation whose extent changes along a flexible torsional coordinate, and which represent the monomer units of polymorphic molecular crystals. Delocalisation error in density functional theory (DFT) adversely impacts conformational energies in these species, overstabilising the conformation that maximises conjugation length and leading to incorrect relative energies for the corresponding crystal polymorphs. We demonstrate that density-corrected (DC-)DFT, in which a DFT exchange-correlation functional is evaluated using a Hartree–Fock density, significantly reduces these conformational energy errors. When DC-DFT monomer energies are used as a low-cost intramolecular correction to a periodic DFT calculation of the molecular crystal, the resulting relative polymorph energies are within 1 kJ/mol of benchmark results.

Polymorphism and Perfection in Crystallization of Hard Sphere Polymers

We present results on polymorphism and perfection, as observed in the spontaneous crystallization of freely jointed polymers of hard spheres, obtained in an unprecedentedly long Monte Carlo (MC) simulation on a system of 54 chains of 1000 monomers. Starting from a purely amorphous configuration, after an initial dominance of the hexagonal closed packed (HCP) polymorph and a transitory random hexagonal close packed (rHCP) morphology, the system crystallizes in a final, stable, face centered cubic (FCC) crystal of very high perfection. An analysis of chain conformational characteristics, of the spatial distribution of monomers and of the volume accessible to them shows that the phase transition is caused by an increase in translational entropy that is larger than the loss of conformational entropy of the chains in the crystal, compared to the amorphous state. In spite of the significant local re-arrangements, as reflected in the bending and torsion angle distributions, the average chain size remains unaltered during crystallization. Polymers in the crystal adopt ideal random walk statistics as their great length renders local conformational details, imposed by the geometry of the FCC crystal, irrelevant.

Polymorphism of Purpurin and Low-level Detection of the Noncentrosymmetric form by Second Harmonic Generation Microscopy

Nonlinear optical imaging based on second harmonic generation (SHG) provides rapid and highly selective detection of polar crystals. Purpurin (PUR) is a natural product with multiple pharmacological activities. Two polymorphs of PUR show distinct crystal packing and structural symmetry, where form I crystallizes in a polar space group and form II crystallizes in a centrosymmetric crystal structure. The two polymorphs are monotropically related, with form I being the thermodynamically stable form, as suggested by slurry experiments, in-situ Raman spectroscopy and crystal structure prediction (CSP). The specificity of SHG to the polar crystals of form I allows rapid polymorphism detection at the limit of individual crystals. SHG is also able to detect low levels of form I in a tablet matrix dominated by amorphous excipients. This study shows that SHG microscopy can achieve the rapid and sensitive detection of noncentrosymmetric crystals in solid dosage forms, which is especially helpful for the early detection of unwanted polymorphic conversion or crystallization of amorphous drugs in formulations and final products.

A phase variety of fluorinated ionic liquids: Molecular conformational and crystal polymorph

Crystal polymorphs of fluorinated ionic liquids (fILs) were examined at low-temperature (LT) by Raman spectroscopy. The fILs were 1-alkyl-3-methylimidazolium perfluorobutanesulfonate, [Cnmim][PFBS] (n = 4, 6, and 8). The cations and anion possess conformational degrees of freedom. Various LT phases were derived from the conformational polymorphs of the cations and the anion. Conformational flexibility depended on alkyl chain length. The crystal polymorphs in the fILs were sensitive to molecular conformations and flexibility.

Polymorphism and grating assembly with unique iridescence features in periodically banded poly(ethylene adipate)

Poly(ethylene adipate) (PEA) forms either ring-banded spherulites (RBS) crystallized between T c = 20–32 °C, or ringless spherulites (RLS) if crystallized away from this range. Morphologies differ correspondingly in their interior structures, as well as polymorphism in that α-form crystal is packed in RLS but combination of α, β crystals are dominantly in ring-banded one. Internal structure of banded spherulites is determined by dissection analyses. Interior lamellae of the banded PEA spherulites are assembled as discontinuous concentric-shell structures with concave shapes like cut onions. The radial-direction plate-like lamellae intersection constitutes each shell with the tangential cilia-like lamellae. Interior tangential lamellae bend or branch out perpendicularly at 90° angle in the radial direction to merge with the radial plate-like lamellae. Through designing optimal regularly-banded morphologies, prominent photonic iridescence is attained in the PEA banded spherulites. Moreover, the PEA banded spherulitic morphology can structured the light with circular pattern by laser interference. Light-interfering grating structures for iridescence applications can be achieved by custom-designing the PEA-RBS assemblies. The interior 3D self-assembly in periodically banded poly(ethylene adipate) is analyzed, and proved to be able to custom-structured as gratings, which, along with the top-surface periodicity, are capable of displaying optical iridescence for potential applications. • PEA spherulite morphology differs correspondingly with variation in polymorphism. • Monomorphic crystal is packed in ringless PEA spherulite but polymorphic crystals are dominantly in ring-banded one. • Interior lamellae of the banded PEA spherulites are assembled as discontinuous cross-hatch gratings. • Light-interference grating structures for iridescence applications can be achieved by custom-designing the PEA-RBS.

Application of functionalized magnetic silica nanoparticles for selective induction of three coumarin metastable polymorphs

The precise control of active pharmaceutical ingredient (API) crystal nucleation and polymorphism is a key consideration in pharmaceutical manufacturing. In this study, tunable nanoparticles were developed to regulate the nucleation process of coumarin. Magnetic silica nanoparticles with four different functional groups (–NH 2 , –COOH, –SH, –NCO) were prepared and coated on the substrate for inducing the crystallization of coumarin. Confined melt crystallization and microspacing sublimation crystallization methods were used to investigate the regulation mechanism. The results indicated that three metastable forms of coumarin can be obtained as pure components based on the combined influence of crystallization methods and functionalized nanoparticles. Form II could be selectively obtained by microspacing sublimation crystallization on Fe 3 O 4 @SiO 2 –SH substrates, and Form IV could be obtained by confined melt crystallization on Fe 3 O 4 @SiO 2 –NCO substrates. Form III could be obtained by further heating Form IV crystals to 52 °C on Fe 3 O 4 @SiO 2 –NCO substrates. Moreover, the polarized light microscopy results also indicated that the introduction of nanoparticles could also increase the stability of the metastable crystalline forms of coumarin. Finally, the diffusion and surface dynamics during nanoparticle induced crystallization were comparatively investigated and the corresponding polymorphic selectivity mechanism was proposed.

Polymorphs with Remarkably Distinct Physical and/or Chemical Properties.

Polymorphism in crystals is known since 1822 and the credit goes to Mitscherlich who realized the existence of different crystal structures of the same compound while working with some arsenate and phosphate salts. Later on, this phenomenon was observed also in organic crystals. With the advent of different technologies, especially the easy availability of single crystal XRD instruments, polymorphism in crystals has become a common phenomenon. Almost 37 % of compounds (single component) are polymorphic to date. As the energies of the different polymorphic forms are very close to each other, small changes in crystallization conditions might lead to different polymorphic structures. As a result, sometimes it is difficult to control polymorphism. For this reason, it is considered to be a nuisance to crystal engineering. It has been realized that the property of a material depends not only on the molecular structure but also on its crystal structure. Therefore, it is not only of interest to academia but also has widespread applications in the materials science as well as pharmaceutical industries. In this review, we have discussed polymorphism which causes significant changes in materials properties in different fields of solid-state science, such as electrical, magnetic, SHG, thermal expansion, mechanical, luminescence, color, and pharmaceutical. Therefore, this review will interest researchers from supramolecular chemistry, materials science as well as medicinal chemistry.

New opportunities for sustainable bioplastic development: Tailorable polymorphic and three-phase crystallization of stereocomplex polylactide by layered double hydroxide

Stereocomplexation between enantiomeric poly(l-lactide) (PLLA) and poly(d-lactide) (PDLA) is a promising sustainable approach and gaining momentum to overcome the shortcomings of polylactide (PLA) for its use as a replacement for fossil-based plastics. Filler addition in tailoring the crystallization of stereocomplex PLA (SC-PLA) has attracted extensive attention; however, research has primarily focused on the heterogeneous nucleation effect of filler. The impact of filler on the chain behavior of SC-PLA during crystallization has not been exclusively discussed, and the rigid amorphous fraction (RAF) development remains unknown. In this study, the crystallization of PLLA/PDLA blends was modified by low loading of layered double hydroxide (LDH) (≤ 1 wt%) with the proposed local effect of such filler, and additional RAF development was incurred. In the early stage of crystallization, LDH facilitates the pairing of PLLA and PDLA and arrests the ordered SC pairs during the dynamic balance between the separation and pairing of racemic segments. This explains the severely suppressed homochiral (HC) crystallization, promoted SC crystallization, and additional RAF formation driven by the nucleation-induced chain ordering. This work, for the first time, highlights the role of LDH in creating SC-PLA with tailorable polymorphism and RAF, where the mechanism can be extended to other filler-type nucleator systems.

Targeted Crystallization of Rare Earth Carbonate Polymorphs at Hydrothermal Conditions via Mineral Replacement Reactions.

The interaction between rare earth element (REE)-rich (La, Pr, Nd, Dy) aqueous solutions, dolomite (CaMg(CO3)2), and aragonite (CaCO3) at low temperature hydrothermal conditions (25-220°C) is studied. The experiments result in the solvent-mediated surface precipitation and subsequent pseudomorphic mineral replacement of the dolomite and aragonite seeds by newly formed REE-carbonates. The host grains are replaced from periphery inward. The newly formed REE-bearing carbonates in La-, Pr-, and Nd-doped systems follow the crystallization sequence: lanthanite [REE2(CO3)3·8H2O] → kozoite [orthorhombic REECO3(OH)] → hydroxylbastnasite [hexagonal REECO3(OH)]. The interaction of Dy-bearing solutions with dolomite results only in the crystallization of kozoite [orthorhombic DyCO3(OH)]. However, experiments with aragonite reveal a two-step crystallization pathway: tengerite [Dy2(CO3)3·2-3(H2O)] → kozoite [orthorhombic DyCO3(OH)]. The temperature, the dissolution rate of the host mineral, and the ionic radii of the REE3+ in question are found to control the kinetics of the replacement reaction, the polymorph selection, and the crystallization pathways toward bastnasite. The findings allow to gain a more in-depth understanding of the formation REE-bearing carbonates, particularly the mineral bastnasite, which is the main source of REEs for industry. This knowledge can be used to improve REE separation, exploration, exploitation methods, as well to produce carbonate minerals with tailored structures.

Deconstructing extra virgin olive oil through fractionation processes

Arbequina monovarietal extra virgin olive oil (EVOO) was fractionated through a multi-step dry fractionation method. Three of the isolated fractions were selected and analyzed: one being liquid at 4 °C, and two being solid at 4 °C, and at 12 °C. Differential scanning calorimetry (DSC) combined with synchrotron radiation X-ray diffraction (SR-XRD) techniques were employed to monitor the polymorphic crystallization and transformation processes when samples were cooled from the melt to complete crystallization and reheated at a rate of 2 °C/min. Fatty acid profiles and α-tocopherol contents were also determined for EVOO and associated fractions. Each sample exhibited a different and unique crystallization and polymorphic behavior, and the number of crystallizing forms and complexity of transitions increased for solid fractions. In more detail, just two polymorphs (β’3-2L and β’2-2L) were detected in the liquid fraction, whereas the fraction which remained in the solid state at 12 °C exhibited six different phases (α-2L; β’3-2L; β’2-2L; β’1-2L; β’2-3L; β’1-3L). These dissimilarities were strongly correlated with meaningful variations in the fatty acid moieties forming TAG structures and caused large deviations in the crystallization and melting temperatures. As an example, melting temperatures of the liquid and the solid fraction at 12 °C were about −3 °C and 17 °C, respectively. It may be worth exploring the potential of EVOO fractions to be used for improving properties of food stuff, among others. The liquid fraction may be of interest due to its high nutritional value owing to elevated contents in monounsaturated fats and antioxidants, whereas the solid fraction at 12 °C may become a good choice to be used as a high-oleic soft fat.

Parts-per-Million Detection of Trace Crystal Forms Using AF-PTIR Microscopy.

Autofluorescence-detected photothermal mid-infrared (AF-PTIR) microscopy was shown to enable parts-per-million detection of α-indomethacin impurity in γ-indomethacin samples. Subtle differences in the photothermal response of the UV-autofluorescence of two indomethacin crystal polymorphs were used for sub-micron chemical discrimination based on fingerprint region mid-IR spectroscopy. The AF-PTIR assignment was independently confirmed by second harmonic generation (SHG) microscopy, which was shown to reduce the total analysis time by rapidly identifying the suitable fields of view. AF-PTIR microscopy has the potential to assist in the early identification of crystal form impurities in the solid dosage forms development pipeline.

Controlling Characteristics of Glycine Crystals by Reactalyzer

Continuous crystallization is the next step of manufacturing especially at the production of pharmaceutical ingredients. We have developed small-scale continuous taylor-vortex crystallizer that is suitable for research in laboratory. But there was a problem that rotating inner cylinder at high-speed range causes much frictional heat and it raises the temperature of the solution, that may spoil the effort of controlling characteristics of crystals. So, we have developed new taylor-vortex crystallizer that has inner cooling system. We conducted several examinations of anti-solvent crystallization of glycine, which aims to obtain unstable crystal polymorph of glycine continuously. The new crystallizer showed the advantage of crystallizing unstable crystal polymorph.

Ordered Submicrometer Structures Developed by Directional Evaporative Crystallization of Acetaminophen in the Presence of Polymers

Crystallization engineering is crucial for the preparation of drug delivery systems with precise release behavior and improved stability. Although evaporation has been commonly used to prepare pharmaceutical film formulations, controlled evaporative crystallization to achieve uniform crystal size and shape has rarely been investigated. In this study, ordered submicrometer composite structures of acetaminophen (ACM) and polymers were prepared via directional evaporative crystallization controlled by a temperature gradient. The ACM crystals had submicrometer sizes while retaining the original crystal polymorph and were aligned along the direction of the temperature gradient, resulting in line structures having branches with uniform and oriented crystal structures. Although the use of a polymer did not affect conventional oven-crystallized films, it significantly decreased the melting point and heat of fusion of directionally crystallized films. The formation of ordered submicrometer composite structures must rely more on kinetic parameters than thermodynamic parameters since no significant intrinsic molecular interactions were discovered. A wide range of sustained-release characteristics could be obtained depending on the polymer types. This unique fast directional crystallization method could offer a new opportunity for future film delivery systems.

Crystal polymorphism in 2,2'-bipyrimidine-based iridium(III) complexes

Mononuclear iridium(III) complexes, NBu4[IrBr4(bpym)] (1) and [IrBr3(bpym)(MeCN)] (2a and 2b) [NBu4 + = tetra(n-butyl)ammonium cation; bpym = 2,2'-bipyrimidine], have been prepared and characterized. Their crystal structures were determined by single-crystal X-ray diffraction. 1 and 2a crystallize in the monoclinic crystal system with space groups P21/c and P21/n, respectively. The 2b phase crystallizes in the orthorhombic crystal system with space group P212121. In these complexes, each iridium(III) is six-coordinate and bonded to two (1) or three (2a and 2b) nitrogen atoms from bpym and MeCN (2a and 2b) molecules and three (2a and 2b) or four (1) bromides. In all the cases, they exhibit a distorted octahedral environment. 2a and 2b display a packing polymorphism containing π···Br, C–H···Br and Br···Br intermolecular interactions. Further analyses of their crystal structures were performed through the SHAPE and CrystalExplorer programs. The electrochemical properties of 1 and 2 were investigated through cyclic voltammetry (CV) technique, with 1 showing a reversible iridium(III)–iridium(IV) redox process.

Implications of particle size on the respective solid-state properties of naltrexone in PLGA microparticles

A thorough understanding of the complexities in formulating and manufacturing polymeric microspheres is required for new and generic drug applications. Specifically, for an ANDA application for polymeric microsphere-based products, the applicant must meet Q1 (qualitative) and Q2 (quantitative) sameness, and in some cases, Q3 (e.g., microstructural) sameness. Herein, we report the naltrexone crystallinity in a PLGA microparticle system prepared from a dichloromethane-benzyl alcohol solvent system results in a crystallinity dependence as a function of microparticle size from the same batch – illustrating intrabatch microstructural variability. As the particle size increases, the crystallinity increases, with additional polymorphic forms more readily noted at the large particle sizes. Furthermore, during dissolution, a polymorphic transition and/or crystallization occurs at larger size fractions. This study highlights the importance of controlling the manufacturing parameters during microparticle formation, specifically solvent extraction and particle size control. Furthermore, with the approval of generic microparticles formulations on the horizon, this study highlights the importance of Q3, the same components in the same concentration with the same arrangement of matter, whereby microparticles can have varying microstructural properties across particle sizes from the same batch.