Stable Β-polymorph Research Articles

The use of polymorphic state modifiers in solid lipid microparticles: The role of structural modifications on drug release performance

This study investigates the correlation between the structural and release properties of solid lipid microparticles (MPs) of tristearin containing 5 % w/w of four different liquid additives used as crystal modifiers: isopropyl myristate (IM), ethyl oleate (EO), oleic acid (OA) and medium chain triglycerides (MCT). All additives accelerated the conversion of the unstable α-form of tristearin, formed after the MPs manufacturing, to the stable β-polymorph and the transformation was completed within 24 h (for IM and EO) or 48 h (for OA and MCT). The kinetic of polymorphic transition at 25 °C was investigated by simultaneous synchrotron SAXS/WAXS and DSC analysis after melting and subsequent cooling of the lipid mixture. After crystallization in the α-phase, additives accelerate the solid-solid phase transformation to β-tristearin. SAXS data showed that two types of structural modifications occurred on MPs during storage: compaction of the crystal packing (slight decrease in lamellar thickness) and crystal growth (increased number of stacked lipid lamellae). The release behavior of a model hydrophilic drug (caffeine) at two different amounts (15 % and 30 %) from MPs was studied in water and biorelevant media simulated the gastric and intestinal environment. It was particularly significant that the introduction of IM, EO and MCT were able to prolong the drug release in water, passing from a diffusion-based Higuchi kinetics to a perfect zero-order kinetic. Moreover, the overall release profiles were higher in biorelevant media, where erosion/digestion of MPs was observed. After 6 months, a moderate but statistically significant change in release profile was observed for the MPs with IM and EO, which can be correlated with the time-dependent structural alterations (i.e. larger average crystallite size) of these formulations; while MPs with OA or MCT displayed stable release profiles. These findings help to understand the correlation between release behavior, polymorphism and supramolecular‐level structural modification of lipid formulations containing crystal modifiers.

Effect of Tween 20 on structure, phase-transition behavior and mechanical properties of monoglyceride oleogels

The aim of this study was to investigate the impact of the addition of a non-gelling non-ionic surfactant, Tween 20 (Tw20), at varying weight ratios with monoglycerides, MGs (0 – 20 g Tw20 to 10 g of MGs as structurant /100 g olive oil) in the crystalline network of the MGs-based oleogels. Several analytical methods such as differential scanning calorimetry (DSC), confocal and polarized optical microscopy, rheometry, and infrared spectroscopy were employed for the characterization of the oleogel structures. The DSC and FT-IR provided evidence that Tween 20 affects the MGs network structure in the oleogels. With addition of Tween 20 the crystal size and the melting/crystallization temperatures of the MGs crystal polymorphs were altered, along with a strengthening of the oleogel structure. Moreover, the presence of Tween 20 in the MGs oleogels accelerated the transformation of the higher free energy crystal forms (α-crystals) to the more thermodynamically stable β-polymorph of the MGs. Apparently, an oil-in-oil emulsion gel is being formed with the MG crystalline entities acting as Pickering particles around the oil/Tween 20 droplets in the oleogel structure. These findings provide valuable information on the synergistic effect of a non-ionic surfactant on monoglyceride-based oleogels, which could be beneficial in constructing multi-component lipid-phases for potential food or cosmetic applications.

Orodispersible Films: A Delivery Platform for Solid Lipid Nanoparticles?

To overcome the poor bioavailability observed for many newly developed active pharmaceutical ingredients (APIs), an appropriate formulation strategy is necessary. One approach is the formulation of these substances in solid lipid nanoparticles and their further processing into solid dosage forms. A promising and innovative oral delivery platform could be orodispersible films (ODFs). ODFs were already investigated more closely, e.g., for the administration of API nanoparticles, and proved their suitability for this formulation approach. The current study was aimed at investigating if the HPMC (hydroxypropyl methyl cellulose) film matrix is also suitable to serve as an appropriate delivery platform for solid lipid nanoparticles. Dependent on the type of triglyceride nanoparticles embedded in the film matrix and the formulation of the lipid particles, lipid contents of up to 54 wt.% could be realized in the film matrix without the loss of the nanoparticulate state. Good mechanical properties were confirmed for these films by determining the tensile strength as well as the elongation before breakage. Interestingly, processing of a lipid suspension into this solid dosage form led to a significantly reduced transformation of the lipid particles from the metastable α- into the stable β-polymorph. This could prove very beneficial when the lipid particles are loaded with APIs.

Liquid Lipids Act as Polymorphic Modifiers of Tristearin-Based Formulations Produced by Melting Technologies.

Despite the growing interest in lipid-based formulations, their polymorphism is still a challenge in the pharmaceutical industry. Understanding and controlling the polymorphic behavior of lipids is a key element for achieving the quality and preventing stability issues. This study aims to evaluate the impact of different oral-approved liquid lipids (LL) on the polymorphism, phase transitions and structure of solid lipid-based formulations and explore their influence on drug release. The LL investigated were isopropyl myristate, ethyl oleate, oleic acid, medium chain trigycerides, vitamin E acetate, glyceryl monooleate, lecithin and sorbitane monooleate. Spray-congealing was selected as an example of a melting-based solvent-free manufacturing method to produce microparticles (MPs) of tristearin (Dynasan®118). During the production process, tristearin MPs crystallized in the metastable α-form. Stability studied evidenced a slow phase transition to the stable β-polymorph overtime, with the presence of the α-form still detected after 60 days of storage at 25 °C. The addition of 10% w/w of LL promoted the transition of tristearin from the α-form to the stable β-form with a kinetic varying from few minutes to days, depending on the specific LL. The combination of various techniques (DSC, X-ray diffraction analysis, Hot-stage polarized light microscopy, SEM) showed that the addition of LL significantly modified the crystal structure of tristearin-based formulations at different length scales. Both the polymorphic form and the LL addition had a strong influence on the release behavior of a model hydrophilic drug (caffeine). Overall, the addition of LL can be considered an interesting approach to control triglyceride crystallization in the β-form. From the industrial viewpoint, this approach might be advantageous as any polymorphic change will be complete before storage, hence enabling the production of stable lipid formulations.

The α-, β-, and γ-polymorphs of polypropylene–polyethylene random copolymer modified by two kinds of β-nucleating agent

The α-, β-, and γ-polymorphs of polypropylene random copolymer with two kinds of β-nucleating agent (TMB-5 and WBG-2) have been studied via wide-angle X-ray diffraction and differential scanning calorimetry. It was found that the addition of 0.5 wt% β-nucleating agent (β-NA) hardly induces appreciable β-modification content, until β-NA content is up to 1 wt%. It seems that low amount of β-NA is not enough to counterbalance the nucleation ability and high content of defects (stereo- and regioerrors) of co-PP, and only α- and γ-modifications are obtained in the samples. Moreover, the relative amount of γ-crystal depends on the crystallization temperature. Although TMB-5 has better heterogeneous nucleation effect than WBG-2, the ability to form stable β-polymorph of WBG-2 is stronger than that of TMB-5. Since large amount of β-nucleation sites overcome the defects of co-PP molecular chain and curb the formation of γ-crystal, competitive growth of α- and β-polymorphs ultimately leads to the coexistence of α- and β-modification.

Effect of cyclophosphamide on the solid form of mannitol during lyophilization

Mannitol is a commonly used bulking agent in lyophilized formulations. It can crystallize into multiple solid forms during lyophilization thereby exhibiting phase heterogeneity and variability in product performance. In this manuscript, we studied the effect of cyclophosphamide (CPA), an anticancer drug, on the solid form of mannitol during lyophilization from aqueous solutions. Freeze-concentration studies were performed in the DSC while lyophilization was performed in a lab scale freeze dryer.DSC experiments revealed two-stage crystallization of mannitol (1.5% w/v) during freeze-concentration, evident as two distinct exothermic events (at −18.2°C and −30°C) in the cooling curve. This was complemented by two eutectic melting endotherms in the subsequent heating curve. Addition of CPA (4.0% w/v) completely inhibited the exotherm at −18.2°C, but enhanced the enthalpy of exotherm at −30°C by five folds. Likewise, only one eutectic melting endotherm was observed in the subsequent heating curve. Lyophilization of the solution containing only mannitol, yielded a mixture of β- (major) and δ- (minor) polymorphs of mannitol. However, in the presence of CPA, only δ-polymorph was observed in the lyophilized sample.This selective favoring of the metastable δ-polymorph over the stable β-polymorph, was explained by altered freezing kinetics of the solution in presence of CPA. The study provides mechanistic insights into solute crystallization behaviour during lyophilization of multi-component systems.

Advanced stable lipid-based formulations for a patient-centric product design

Multiparticulate dosage forms are a recent strategy to meet the special needs of children, elderly people and patients suffering from dysphagia. Our study presents a novel and cost-efficient approach for the manufacturing of a taste-masked multiparticulate system with a stable immediate release profile by applying lipid-based excipients in a solvent-free hot melt coating process.The thermosensitive N-acetylcysteine (N-ac) was used as model drug and hot-melt coated with a mixture of tripalmitin and polysorbate 65.A predictive in vitro method for the evaluation of the taste masking efficiency was developed based on the deprotonation of the carboxyl group of N-ac and the decline of pH, responsible for the unpleasant sour taste of the compound. The method was confirmed using in vivo studies. Differential scanning calorimetry and X-ray scattering experiments revealed polymorphic transformation and its dependency on transformation time, temperature and emulsifier concentration. During the process, the coating was transformed almost completely into the stable β-polymorph, leading to an unaltered dissolution profile during storage. A statistical design was conducted that revealed the critical process parameters affecting the taste masking efficiency and drug release.This study shows the successful application of solvent-free hot-melt coating in the development of a taste-masked and stable formulation.

Stability of the Metastable α-Polymorph in Solid Triglyceride Drug-Carrier Nanoparticles.

Colloidal dispersions of crystalline nonpolar lipids are under intensive investigation as carrier systems in pharmaceutics and nutrition. In this context, the controlled preparation of particles in a metastable polymorphic state is of some interest for the delivery of active substances. In the present study, tristearin particles stabilized with three α-polymorph-preserving emulsifier regimes ((I) sodium glycocholate/saturated long-chain phospholipids, (II) sodium glycocholate, and (III) poly(vinyl alcohol) (PVA)) were investigated concerning the stability of the metastable α-polymorph after controlled crystallization of the particles from the melt. Upon long-term storage, the α-polymorph was preserved best in PVA-stabilized dispersions, followed by those stabilized with the glycocholate/phospholipid mixture and finally those stabilized solely with the bile salt. In particular for rapidly crystallized nanoparticles, the formation of an α-polymorph with highly reduced lamellarity was observed. According to time-/temperature-resolved synchrotron X-ray diffraction analysis with simultaneous DSC (differential scanning calorimetry) studies, this less-ordered α-polymorph transformed into the common, lamellar α-form upon heating. Although the presence of the less-ordered form is probably related to the extraordinarily high stability of the metastable α-polymorph observed in some of the dispersions, it could not completely prevent the transition into the stable β-polymorph. The higher the transition temperature of the less-ordered α-form to the ordered one, the slower was the polymorphic transition to the stable β-polymorph. To estimate the polymorphic stability of the differently stabilized particles upon isothermal long-term storage, standard DSC measurements on samples stored at 23 °C for 4 weeks seem to be of predictive value.

Pressure-tuning micro-Raman spectra of artists’ pigments: α- and β-copper phthalocyanine polymorphs

The two polymorphs of copper phthalocyanine, α- and β-CuPc, have been examined by micro-Raman spectroscopy at pressures approaching 5.0GPa. The metastable α-polymorph does not exhibit any structural changes, while the more thermodynamically stable β-polymorph does exhibit a reversible phase transition at 2.0GPa. The pressure dependences (dν/dP) for a selected number of vibrational modes are reported. Two regions of the Raman spectra, 800–900cm−1 and 1100–1200cm−1, are sensitive to pressure such that they can be used as indicators of the polymorphic form.

Functionalized Silica Nanoparticles as Additives for Polymorphic Control in Emulsion-Based Crystallization of Glycine

Emulsion-based crystallization to produce spherical crystalline agglomerates is an attractive route to control the size and morphology of active pharmaceutical ingredient (API) crystals, which in turn improves downstream processability. Here, we demonstrate the use of silica nanoparticles modified with different surface functional groups (hydroxyl, amino, carboxylic, imidazolim chloride, and chloride) as additives in water-in-oil emulsion-based crystallization of glycine, a model API molecule. Spherical agglomerates of glycine obtained under different experimental conditions are characterized by powder X-ray diffraction (XRD) and scanning electron microscopy. Our observations reveal the strong influence of particle functionalization on polymorphic outcome at near-neutral (pH ∼6) conditions, where we are able to selectively crystallize the least stable β-polymorph of glycine or tune the relative ratio of α- and β-polymorphs by selecting appropriate experimental conditions. Mixtures of α- and γ-glycine are typically obtained under acidic solutions (pH ∼3), irrespective of the functional groups used. We examine the influence of charge and immobilization density of surface functional groups and nanoparticle concentration on the polymorphic outcome and rationalize our results by analyzing molecular and functional group speciation.

Nucleation control, separation and bulk growth of metastable α-l-glutamic acid single crystals in the presence of l-tyrosine

The nucleation control and separation of the metastable α-l-glutamic acid polymorph from aqueous solution was successfully carried out in the presence of the selective additive l-tyrosine. The influence of different additive concentrations on the solubility, pH and nucleation time of l-glutamic acid polymorphs was revealed. It is found that below a critical level of concentration (<0.07g/100ml), the incorporated additive suppresses the nucleation of the commonly occurring stable β-polymorph effectively and promotes the nucleation of rarely occurring metastable α polymorph. Above the critical level, the additive suppresses completely the nucleation of both α- and β-polymorphs in the solution. For the first time, a bulk single crystal measuring size of 20×11×8mm3 of the metastable α-l-glutamic acid was successfully grown from aqueous solution in the presence of an optimized concentration of l-tyrosine by the slow cooling method with the reversible seed rotation technique. Morphology of the grown crystals was revealed in accordance with equilibrium morphology. X-ray powder diffraction and single crystal structural refinement studies reveal that the incorporated additive molecules do not alter or enter into the crystal lattices but plays their inhibitory role only by just making their presence in the solution.

Control of polymorphism and crystal size of L-glutamic acid in the absence of additives

Slow cooling of a supersaturated solution of L-glutamic acid, with continuous or pulsed agitation during cooling, is sufficient to stabilise the α-polymorph for crystallisation times of 24 h at 45 °C. Rapid cooling with agitation or slow cooling without agitation favours formation of the stable β-polymorph. A reduction in average particle size and crystal quality of the α-crystals was observed following agitation and there was a marked absence of β-inclusions on the surface of and inside the α-crystals under these conditions. Two hypotheses are presented to explain the stabilisation of the α-polymorph namely, (i) that agitation is sufficient to disrupt nucleation of the β-crystals on the surface of the α-crystals and (ii) that α-crystals formed with agitation during slow cooling are small and poorly formed and lack the necessary well-formed crystallographic facets on which the β-form can nucleate. That the β-polymorph is favoured during rapid cooling with agitation can be explained in terms of the reduced period of agitation.

Polymorphism of dehydrocholic acid: crystal structure of the β-phase and guest-mediated solid phase conversion

Dehydrocholic acid may be obtained in two polymorphic forms: α and β. The complete characterization and the crystal structure of the β-phase (obtained by unconventional powder diffraction methods) are described and discussed. Conversion of the α-form into the thermodynamically more stable β-polymorph may be obtained through a room temperature solvent-mediated process. On the other hand, transformation of the β-form into the α-form is realized through two distinct pathways: via a temperature-mediated process or as a guest-mediated solid state conversion, without the intervention of an amorphous state. R-(+)-Methyl p-tolyl sulfoxide is the guest of choice for this unusual β-to-α transformation.

Observation of Size-Dependent Melting in Lipid Nanoparticles

The differential scanning calorimetry thermograms of suspensions of trimyristin nanoparticles in the stable β-polymorph display several melting events. Particle thickness distributions obtained by ...

X-Form metal-free phthalocyanine: crystal structure determination using a combination of high-resolution X-ray powder diffraction and molecular modelling techniques

A combination of high resolution X-ray diffraction and molecular modelling techniques have been used to determine (Rwp= 12.51%) the crystal structure of the X-form of metal-free phthalocyanine. It was found to crystallise in a bimolecular monoclinic unit cell (space group P21/a) with lattice parameters a= 10.63, b= 23.15, c= 4.89 Å, β= 95.98° in a ‘herring-bone’ molecular packing motif with a smaller angle (50°) than is found in the more stable β-polymorph (89°).

Thermoanalysis of the recrystallization process of melt-homogenized glyceride nanoparticles

The recrystallization behaviour, the time course of polymorphic transitions, and the degree of crystallinity of melthomogenized glyceride nanoparticle dispersions were investigated by differential scanning calorimetry (DSC). The results suggest that these properties of the nanoparticles are different from those of the glyceride bulk materials. Crystallization of the molten emulsified glycerides tripalmitate and hard fat in the dispersed state occurs about 20 °C lower than in the bulk. The melting temperature of the colloidal crystalline particles is lowered as much as 12 °C. Unambiguous interpretation of DSC thermograms is only possible using the information about the crystalline modification of the glyceride nanoparticles obtained by X-ray diffraction studies. The lower degree of crystallinity of the dispersed lipids compared to bulk materials is reflected in the reduced heat of fusion of the glyceride nanoparticles. The polymorphic transitions are accelerated in glyceride nanoparticles as compared to their bulk materials and the effect depends on the emulsifier and its concentration. The crystallinity index of hard fat nanoparticles is lower than that of tripalmitate nanoparticles. Incorporation of the model drug ubidecarenone into different lipid matrices resulted in a decreased crystallinity as well as in a delayed transition of residual α-polymorphic material into the stable β-polymorph. The latter effect was also observed for incorporation of glycerol monostearate. The DSC results can be explained in terms of the colloidal nature of the dispersions and the influence of foreign compounds such as emulsifiers, drugs and impurities.

Time resolved x-ray diffraction studies of the polymorphic behaviour of tripalmitin using synchrotron radiation

The polymorphic behaviour of the monoacid triglyceride, tripalmitin was studied by time resolved X-ray diffraction experiments involving synchrotron radiation. Fast crystallization processes and phase transitions can be investigated under conditions identical to those in differential scanning calorimetry (DSC). Upon melting of the α-phase, recrystallization occurs in the β-phase with the intervention of a very unstable β′-phase. During the melting process of the α-phase, the lamellar organization of the molcules (along the c-axis of the crystal cell) remains intact and is only destroyed after melting of the most stable β-polymorph. The melting process of the α-phase is merely restricted to a disordering at the atomic level (in the a– b-plane of the crystal cell). For tripalmitin, the β′-phase can only be prepared if crystallization is performed from the isotropic melt. Although the existence of more than one β′-phase is confirmed, no clear experimental evidence is available to prove unambiguously the existence of two distinct and independent β′-polymorphs. Both β′-phases seem to differ only in crystal perfection and crystallinity. In this context, crystallinity is defined as the degree to which the enthalpy of the unit cell approaches its theoretical minimum. A similar situation is found for the β-phase. Depending on the thermal conditions under which the β-form is crystallized, the β-phase can exhibit large differences in thermal characteristics, which can also be explained in terms of crystal perfection and crytallinity. The polymorphic transitions seem to take place from α to β′ and then further to β, with the transitions being mainly expressed as changes in lateral arrangements of the dimeric unit. During the polymorphic transitions, the change in lateral structure first takes place along the b-axis, followed by a delayed rearrangement along the a-axis of the crytallographic unit cell.

Influence of physicochemical interactions on the properties of suppositories I. Interactions between the constituents of fatty suppository bases

Using differential thermal analysis (DTA) the increase in melting point on storage of fatty suppository bases was found to be closely associated with the conversion of the α-and β'-polymorphs of the constituent bases to the more stable β-polymorph. The rate of this process was found to decrease with increasing chain length. The phase diagrams of binary mixtures of tricaprin, trilaurin, trimyristin, tripalmitin and tristearin showed eutectic or monotectic behaviour. For each ·CH 2-CH 2· increment in side-chain length by which the two triglycerides differ, the eutectic composition was reduced by about 20% (w/w) with respect to the higher melting component. The lower the chain length (and melting point) of the glycerides in the binary mixtures, the closer the agreement in melting point determined by U-tube, open tube or DTA methods. The thermal data enabled the following binary mixtures of pure triglycerides to be proposed as suppository bases: 2–8% (w/w) tristearin in tricaprin; 3–10% (w/w) tripalmitin in tricaprin; 10–25% (w/w) trimyristin in tricaprin; 55–65% (w/w) trilaurin in tricaprin; 40% (w/w) trilaurin in tricaprin.