Surface Mediated Structures: Stabilization of Metastable Polymorphs on the Example of Paracetamol

The preparation of typically thermodynamically unstable polymorphic structures is a challenge. However, solid surfaces are well established aids for the formation and stabilization of polymorphic structures within, for instance, organic electronics. In this study, we report the stabilization of a pharmaceutically relevant substance via a solid surface at ambient conditions. Form III of paracetamol, which is typically unstable in the bulk at standard conditions, can be stabilized with a model silica surface by a standard spin coating procedure followed by rapid heat treatment. Such a preparation technique allows the use of atomic force microscopy and grazing incidence X-ray diffraction measurements revealing detailed information on the morphology and structure of the polymorph. Furthermore, the results exhibit that this polymorph is stable over a long period of time revealing surface mediated stabilization. These findings demonstrate a novel approach to provide thermodynamic stability when applied to similar molecules with specific applications

Crystal Growth Alignment of β‑Polymorph of Resorcinol in Thermal Gradient

Crystallization of an organic compound, namely, resorcinol, has been studied in a thermal gradient over a substrate where samples are, in addition, mechanically displaced at a constant rate. In such an experiment, nucleation and growth occur in well-defined dissipative conditions. The results show the capability of this method to produce thin films in the resorcinol β-form. Further, the alignment of the crystals within these films is along a preferred orientation. Employing polarized optical microscopy and X-ray diffraction measurements in terms of specular diffraction and pole figures shows that the crystals alignment follows the thermal gradient. Variation of the displacement rate, i.e., the sample velocity in the gradient field, shows additionally strong variation of the crystal orientations, showing that the kinetic of the crystal formation is crucial for the alignment in the thermal gradient

Polymer Encapsulation of an Amorphous Pharmaceutical by initiated Chemical Vapor Deposition for Enhanced Stability

The usage of amorphous solids in practical applications, such as in medication, is commonly limited by the poor long-term stability of this state, because unwanted crystalline transitions occur. In this study, three different polymeric coatings are investigated for their ability to stabilize amorphous films of the model drug clotrimazole and to protect against thermally induced transitions. For this, drop cast films of clotrimazole are encapsulated by initiated chemical vapor deposition (iCVD), using perfluorodecyl acrylate (PFDA), hydroxyethyl methacrylate (HEMA), and methacrylic acid (MAA). The iCVD technique operates under solvent-free conditions at low temperatures, thus leaving the solid state of the encapsulated layer unaffected. Optical microscopy and X-ray diffraction data reveal that at ambient conditions of about 22 °C, any of these iCVD layers extends the lifetime of the amorphous state significantly. At higher temperatures (50 or 70 °C), the p-PFDA coating is unable to provide protection, while the p-HEMA and p-MAA strongly reduce the crystallization rate. Furthermore, p-HEMA and p-MAA selectively facilitate a preferential alignment of clotrimazole and, interestingly, even suppress crystallization upon a temporary, rapid temperature increase (3 °C/min, up to 150 °C). The results of this study demonstrate how a polymeric coating, synthesized directly on top of an amorphous phase, can act as a stabilizing agent against crystalline transitions, which makes this approach interesting for a variety of applications

Solvent Vapor Annealing of Amorphous Carbamazepine Films for Fast Polymorph Screening and Dissolution Alteration

Solubility enhancement and thus higher bioavailability are of great importance and a constant challenge in pharmaceutical research whereby polymorph screening and selection is one of the most important tasks. A very promising approach for polymorph screening is solvent vapor annealing where a sample is exposed to an atmosphere saturated with molecules of a specific chemical/solvent. In this work, amorphous carbamazepine thin films were prepared by spin coating, and the transformation into crystalline forms under exposure to solvent vapors was investigated. Employing grazing incidence X-ray diffraction, four distinct carbamazepine polymorphs, a solvate, and hydrates could be identified, while optical microscopy showed mainly spherulitic morphologies. <i>In vitro</i> dissolution experiments revealed different carbamazepine release from the various thin-film samples containing distinct polymorphic compositions: heat treatment of amorphous samples at 80 °C results in an immediate release; samples exposed to EtOH vapors show a drug release about 5 times slower than this immediate one; and all the others had intermediate release profiles. Noteworthy, even the sample of slowest release has a manifold faster release compared to a standard powder sample demonstrating the capabilities of thin-film preparation for faster drug release in general. Despite the small number of samples in this screening experiment, the results clearly show how solvent vapor annealing can assist in identifying potential polymorphs and allows for estimating their impact on properties like bioavailability

Complex Behavior of Caffeine Crystallites on Muscovite Mica Surfaces

Defined fabrication of organic thin films is highly desired in technological, as well as pharmaceutical, applications since morphology and crystal structure are directly linked to physical, electrical, and optical properties. Within this work, the directed growth of caffeine deposited by hot wall epitaxy (HWE) on muscovite mica is studied. Optical and atomic force microscopy measurements reveal the presence of caffeine needles exhibiting a preferable alignment in the azimuthal directions with respect to the orientation of the defined mica surface. Specular X-ray diffraction and X-ray diffraction pole figure measurements give evidence that the β-polymorphic form of caffeine forms on the mica surface. All results consent that caffeine molecules have an edge-on conformation i.e. minimizing their interaction area with the surface. Furthermore, the azimuthal alignment of the long caffeine needle axis takes place along the [11̅0], [100], and [110] real space directions of mica; needles are observed every 60° azimuthally. While mica has a complex surface structure with mirror planes and lowered oxygen rows, the slightly disturbed 3-fold symmetry dictates the crystal alignment. This is different to previous findings for solution cast caffeine growth on mica. For HWE the needles align solely along the mica main directions whereby solution cast needles show an additional needle splitting due to a different alignment of caffeine with respect to the surface

Bulk and Surface-Stabilized Structures of Paracetamol Revisited by Raman Confocal Microscopy

We revisit the polymorphism of paracetamol by means of a micro-Raman technique, which has proved to be a powerful tool for structure recognition. Distinct lattice phonon spectra clearly identified the pure phases. Confocality enabled us to detect phase mixing between form II and either I or III on a micrometric scale in the same crystallite. Following the most recent findings on surface-mediated structures, we also investigated spin-coated films grown on glass, gold, and polystyrene substrates, confirming the selectivity of these surfaces for the metastable form III, which shows an unprecedented stability over a time span of several months. A mechanism of its transformation to phase II, via a partially ordered intermediate state, is suggested by polarized Raman measurements

Crystallographic Textures and Morphologies of Solution Cast Ibuprofen Composite Films at Solid Surfaces

The preparation of thin composite layers has promising advantages in a variety of applications like transdermal, buccal, or sublingual patches. Within this model study the impact of the matrix material on the film forming properties of ibuprofen–matrix composite films is investigated. As matrix materials polystyrene, methyl cellulose, or hydroxyl-ethyl cellulose were used. The film properties were either varied by the preparation route, i.e., spin coating or drop casting, or via changes in the relative ratio of the ibuprofen and the matrix material. The resulting films were investigated via X-ray diffraction and atomic force microscope experiments. The results show that preferred (100) textures can be induced via spin coating with respect to the glass surface, while the drop casting results in a powder-like behavior. The morphologies of the films are strongly impacted by the ibuprofen amount rather than the preparation method. A comparison of the various matrix materials in terms of their impact on the dissolution properties show a two times faster zero order release from methyl cellulose matrix compared to a polystyrene matrix. The slowest rate was observed within the hydroxyl ethyl cellulose as the active pharmaceutical ingredients (APIs) release is limited by diffusion through a swollen matrix. The investigation reveals that the ibuprofen crystallization and film formation is only little effected by the selected matrix material than that compared to the dissolution. A similar experimental approach using other matrix materials may therefore allow to find an optimized composite layer useful for a defined application

One Polymorph and Various Morphologies of Phenytoin at a Silica Surface Due to Preparation Kinetics

The preparation of solid crystalline films at surfaces is of great interest in a variety of fields. Within this work the preparation of pharmaceutically relevant thin films containing the active pharmaceutical ingredient phenytoin is demonstrated. The preparation techniques applied include drop casting, spin coating, and vacuum deposition. For the solution processed samples a decisive impact of the solution concentration and the applied film fabrication technique is observed; particular films form for all samples but with their extensions along different crystallographic directions strongly altered. Vacuum deposition of phenytoin reveals amorphous films, which over time crystallize into needle-like or particular-type structures whereby a nominal thickness of 50 nm is required to achieve a fully closed layer. Independent of all preparation techniques, the resulting polymorph is the same for each sample as confirmed by specular X-ray diffraction scans. Thus, morphologies observed via optical and atomic force microscope techniques are therefore a result of the preparation technique. This shows that the different time scales for which crystallization is obtained is the driving force for the various morphologies in phenytoin thin films rather than the presence of another polymorph forming

Manufacturing of a Secretoneurin Drug Delivery System with Self-Assembled Protamine Nanoparticles by Titration

<div><p>Since therapeutic peptides and oligonucleotides are gathering interests as active pharmaceutical ingredients (APIs), nanoparticulate drug delivery systems are becoming of great importance. Thereby, the possibility to design drug delivery systems according to the therapeutic needs of APIs enhances clinical implementation. Over the last years, the focus of our group was laid on protamine-oligonucleotide-nanoparticles (so called proticles), however, the possibility to modify the size, zeta potential or loading efficiencies was limited. Therefore, at the present study we integrated a stepwise addition of protamine (titration) into the formation process of proticles loaded with the angiogenic neuropeptide secretoneurin (SN). A particle size around 130 nm was determined when proticles were assembled by the commonly used protamine addition at once. Through application of the protamine titration process it was possible to modify and adjust the particle size between approx. 120 and 1200 nm (dependent on mass ratio) without influencing the SN loading capacity. Dynamic light scattering pointed out that the difference in particle size was most probably the result of a secondary aggregation. Initially-formed particles of early stages in the titration process aggregated towards bigger assemblies. Atomic-force-microscopy images also revealed differences in morphology along with different particle size. In contrast, the SN loading was only influenced by the applied mass ratio, where a slight saturation effect was observable. Up to 65% of deployed SN could be imbedded into the proticle matrix. An in-vivo biodistribution study (i.m.) showed a retarded distribution of SN from the site of injection after the application of a SN-proticle formulation. Further, it was demonstrated that SN loaded proticles can be successfully freeze-dried and resuspended afterwards. To conclude, the integration of the protamine titration process offers new possibilities for the formulation of proticles in order to address key parameters of drug delivery systems as size, API loading or modified drug release.</p></div

Development of zeta potential throughout protamine titration.

<p>Particles were assembled without SN (blank marks) or 100 μg/ml SN (filled marks), as well as with 150 μg/ml protamine (blue lines) or 300 μg/ml (red lines). The ODN concentration was set to 100 μg/ml, each undiluted sample was measured at least in duplicate.</p