Publications by authors named "Karol Nartowski"

16 Publications

  • Page 1 of 1

Emulsion-Based Multicompartment Vaginal Drug Carriers: From Nanoemulsions to Nanoemulgels.

Int J Mol Sci 2021 Jun 16;22(12). Epub 2021 Jun 16.

Department of Drug Form Technology, Wroclaw Medical University, Borowska 211 A, 50-556 Wroclaw, Poland.

In order to overcome the limitations associated with vaginal administration of drugs, e.g., the short contact time of the drug form with the mucosa or continuous carrier wash-out, the development of new carriers for gynecological use is necessary. Furthermore, high individual anatomical and physiological variability resulting in unsatisfactory therapeutic efficacy of lipophilic active substances requires application of multicompartment drug delivery systems. This manuscript provides an up-to-date comprehensive review of the literature on emulsion-based vaginal dosage forms (EVDF) including macroemulsions, microemulsions, nanoemulsions, multiple emulsions and self-emulsifying drug delivery systems. The first part of the paper discusses (i) the influence of anatomical-physiological conditions on therapeutic efficacy of drug forms after local and systemic administration, (ii) characterization of EVDF components and the manufacturing techniques of these dosage forms and (iii) methods used to evaluate the physicochemical and pharmaceutical properties of emulsion-based vaginal dosage forms. The second part of the paper presents (iv) the results of biological and in vivo studies as well as (v) clinical evaluation of EVDF safety and therapeutic efficacy across different indications.
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http://dx.doi.org/10.3390/ijms22126455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233730PMC
June 2021

Stabilisation and Growth of Metastable Form II of Fluconazole in Amorphous Solid Dispersions.

Pharmaceutics 2019 Dec 20;12(1). Epub 2019 Dec 20.

Department of Drug Forms Technology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland.

The crystallisation of metastable drug polymorphs in polymer matrices has been reported as a successful approach to enhance the solubility of poorly water-soluble drug molecules. This can be achieved using different polymers, drug to polymer ratios and formulation techniques enabling the formation of stable nuclei and subsequent growth of new or metastable drug polymorphs. In this work we elucidated the polymorphism behaviour of a model compound fluconazole (FLU) embedded in solid dispersions with amorphous Soluplus (SOL) obtained using spray drying and fusion methods. The effect of humidity on the stability of FLU in the obtained dispersions was also evaluated. FLU at a drug content below 40 wt. % stayed amorphous in the dispersions prepared using the fusion method and crystallised exclusively into metastable form II at a drug content above 40 wt. % and 70% relative humidity (RH) conditions. In contrast, a mixture of forms I, II and hydrate of FLU was detected in the spray dried formulations after 14 days of storage at 40 °C/40% RH, with preferential growth of thermodynamically stable form I of FLU. This study highlights the importance of preparation techniques and the drug:polymer ratio in the formulation of amorphous solid dispersions and provides further understanding of the complex crystallisation behaviour of amorphous pharmaceuticals encapsulated in the polymer matrixes.
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http://dx.doi.org/10.3390/pharmaceutics12010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023302PMC
December 2019

Tuning the cocrystal yield in matrix-assisted cocrystallisation via hot melt extrusion: A case of theophylline-nicotinamide cocrystal.

Int J Pharm 2019 Oct 27;569:118579. Epub 2019 Jul 27.

Department of Drug Form Technology, Wroclaw Medical University, Wroclaw, Poland.

Polymer-assisted cocrystallisation via hot melt extrusion (HME) facilitates the cocrystallisation process and increases cocrystal yield compared with the HME of neat cocrystal components. This makes it an attractive method for the single-step continuous synthesis of pharmaceutical cocrystals. The aim of this study is to understand the effect of semicrystalline (Poloxamer P407, PXM) or amorphous (Soluplus®, SOL) polymers on the cocrystallisation of model theophylline-nicotinamide (TP:NA, 1:1) cocrystal with significantly different melting temperatures of API (TP, m.p. = 271.4 °C) and coformer (NA, m.p. = 128.7 °C) in neat and matrix-assisted cocrystallisation via HME. Compared with the processing of neat cocrystal components, the addition of PXM led to formulation of TP:NA cocrystal embedded in the polymer matrix and increased the cocrystal formation efficiency. On the other hand, the co-processing of cocrystal components with SOL resulted in the formation of cocrystal embedded in the amorphous polymer matrix or in the partially amorphous TP:NA/SOL composites. The one-step formulation of API:coformer mixtures with polymers using HME may result in phase changes or the formation of amorphous solid dispersions, which highlights the importance of matrix selection and phase control of the final product.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118579DOI Listing
October 2019

Continuous, one-step synthesis of pharmaceutical cocrystals via hot melt extrusion from neat to matrix-assisted processing - State of the art.

Int J Pharm 2019 Mar 18;558:426-440. Epub 2019 Jan 18.

Department of Drug Form Technology, Wroclaw Medical University, Wroclaw, Poland.

Use of hot melt extrusion (HME) as continuous manufacturing process in the cocrystal synthesis is of increasing interest from both industrial and academic perspective and it is seen as a newly developing branch of mechanochemistry with possible broad application in single step synthesis and formulation of pharmaceutical cocrystals. Furthermore, one-step formulation of pharmaceutical products results in combined processing of pharmaceutical cocrystal mixtures with polymers using HME, which may result in phase change or formation of amorphous solid dispersions during the material processing. The manuscript aims at providing selection guidelines and understanding of processing parameters and instrumental setup of importance to design the HME process for cocrystal synthesis. Furthermore, importance of stoichiometry control of the final product and the matrix selection criteria in simultaneous synthesis and formulation of pharmaceutical cocrystals via HME are provided. The first part of this review, introduce mechanochemical methods of cocrystals synthesis along brief explanation of the possible molecular mechanisms of cocrystal synthesis via mechanochemical approach. Subsequently, the critical process parameters i.e. temperature, screw speed, screw configuration or material feed rate of importance in successful synthesis of high quality product are described followed by literature examples of the processing of neat cocrystal compounds or matrix assisted cocrystallisation.
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http://dx.doi.org/10.1016/j.ijpharm.2019.01.016DOI Listing
March 2019

Nanocrystallization of Rare Tolbutamide Form V in Mesoporous MCM-41 Silica.

Mol Pharm 2018 11 8;15(11):4926-4932. Epub 2018 Oct 8.

School of Pharmacy , University of East Anglia , Norwich Research Park, Norwich NR4 7TJ , U.K.

Encapsulation of pharmaceuticals inside nanoporous materials is of increasing interest due to their possible applications as new generation therapeutics, theranostic platforms, or smart devices. Mesoporous silicas are leading materials to be used as nanohosts for pharmaceuticals. Further development of new generation of nanoscale therapeutics requires complete understanding of the complex host-guest interactions of organic molecules confined in nanosized chambers at different length scales. In this context, we present results showing control over formation and phase transition of nanosize crystals of model flexible pharmaceutical molecule tolbutamide confined inside 3.2 nm pores of the MCM-41 host. Using low loading levels (up to 30 wt %), we were able to stabilize the drug in highly dynamic amorphous/disordered state or direct the crystallization of the drug into highly metastable nanocrystalline form V of tolbutamide (at loading levels of 40 and 50 wt %), providing first experimental evidence for crystallization of pharmaceuticals inside the pores as narrow as 3.2 nm.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00575DOI Listing
November 2018

The role of the polymer matrix in solvent-free hot melt extrusion continuous process for mechanochemical synthesis of pharmaceutical cocrystal.

Eur J Pharm Biopharm 2018 Oct 3;131:48-59. Epub 2018 Jul 3.

Department of Drug Form Technology, Wroclaw Medical University, Wroclaw, Poland. Electronic address:

Solid-state synthesis of pharmaceutical cocrystals is of contemporary interest as it offers an efficient way to modify the physicochemical properties of Active Pharmaceutical Ingredient (API) including its melting point, solubility, compressibility or physical stability, without compromising its structural integrity and bioactivity. Therefore, research of novel and emerging techniques for solvent-free, continuous and scalable methods for cocrystal formation is of paramount importance for further industrial development. In this work we form a basis for knowledge-based synthesis and formulation of model pharmaceutical cocrystal (flufenamic acid, FFA: nicotinamide, NA; 1:1) via matrix-assisted cocrystallisation (MAC) using Hot Melt Extrusion (HME). Five different polymers frequently used in pharmaceutical drug delivery: Poloxamer P407 (PXM), PEG-PVA copolymer, Soluplus® (SOL), PVPVA64 and HPMCAS with different structural features and physicochemical properties were investigated as functional matrices for FFA:NA cocrystal synthesis via HME. Significant decrease of the torque value during MAC process was observed for all investigated polymers as compared to extrusion of neat FFA:NA cocrystal. The FFA:NA cocrystal encapsulated in the polymer matrix was successfully formed using semicrystalline PXM and PEG-PVA polymers at all investigated FFA:NA/polymer ratios. The use of amorphous polymers (SOL, PVPVA64, HPMCAS) as a cocrystallisation matrix resulted in formation of FFA:NA cocrystal embedded in an amorphous FFA:NA/polymer matrix (at polymer contents of 10 and 20 wt.%) or FFA:NA/polymer amorphous composites at SOL and PVPVA64 content of 30 wt.%. Furthermore, the significant increase of FFA dissolution was observed for FFA:NA cocrystal encapsulated in PXM and PEG-PVA matrices as compared to neat FFA form I. FFA form III and FFA:NA cocrystal. The presented work enables for the first time knowledge-based approach for simultaneous synthesis and formulation of pharmaceutical cocrystals via Hot Melt Extrusion a solvent-free, scalable and continuous process.
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http://dx.doi.org/10.1016/j.ejpb.2018.07.002DOI Listing
October 2018

Halogen effects on the solid-state packing of phenylalanine derivatives and the resultant gelation properties.

Faraday Discuss 2017 10;203:423-439

School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK.

Phenylalanine is an important amino acid both biologically, essential to human health, and industrially, as a building block of artificial sweeteners. Our interest in this particular amino acid and its derivatives lies with its ability to form gels in a number of solvents. We present here the studies of the influence of halogen addition to the aromatic ring on the gelation properties and we analyse the crystal structures of a number of these materials to elucidate the trends in their behaviour based on the halogen addition to the aromatic group and the interactions that result.
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http://dx.doi.org/10.1039/c7fd00108hDOI Listing
October 2017

Supramolecular Amino Acid Based Hydrogels: Probing the Contribution of Additive Molecules using NMR Spectroscopy.

Chemistry 2017 Jun 23;23(33):8014-8024. Epub 2017 May 23.

School of Pharmacy, University of East Anglia, Norwich Research Park, NR4 7TJ, UK.

Supramolecular hydrogels are composed of self-assembled solid networks that restrict the flow of water. l-Phenylalanine is the smallest molecule reported to date to form gel networks in water, and it is of particular interest due to its crystalline gel state. Single and multi-component hydrogels of l-phenylalanine are used herein as model materials to develop an NMR-based analytical approach to gain insight into the mechanisms of supramolecular gelation. Structure and composition of the gel fibres were probed using PXRD, solid-state NMR experiments and microscopic techniques. Solution-state NMR studies probed the properties of free gelator molecules in an equilibrium with bound molecules. The dynamics of exchange at the gel/solution interfaces was investigated further using high-resolution magic angle spinning (HR-MAS) and saturation transfer difference (STD) NMR experiments. This approach allowed the identification of which additive molecules contributed in modifying the material properties.
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http://dx.doi.org/10.1002/chem.201700793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575562PMC
June 2017

Structure and Mobility of Lactose in Lactose/Sodium Montmorillonite Nanocomposites.

Langmuir 2016 12 29;32(49):13214-13225. Epub 2016 Nov 29.

Department of Pharmacy, Uppsala University , 751 23 Uppsala, Sweden.

This study aims at investigating the molecular level organization and molecular mobility in montmorillonite nanocomposites with the uncharged organic low-molecular-weight compound lactose commonly used in pharmaceutical drug delivery, food technology, and flavoring. Nanocomposites were prepared under slow and fast drying conditions, attained by drying at ambient conditions and by spray-drying, respectively. A detailed structural investigation was performed with modulated differential scanning calorimetry, powder X-ray diffraction, solid-state nuclear magnetic resonance spectroscopy, scanning electron microscopy, microcalorimetry, and molecular dynamics simulations. The lactose was intercalated in the sodium montmorillonite interlayer space regardless of the clay content, drying rate, or humidity exposure. Although, the spray-drying resulted in higher proportion of intercalated lactose compared with the drying under ambient conditions, nonintercalated lactose was present at 20 wt % lactose content and above. This indicates limitations in maximum loading capacity of nonionic organic substances into the montmorillonite interlayer space. Furthermore, a fraction of the intercalated lactose in the co-spray-dried nanocomposites diffused out from the clay interlayer space upon humidity exposure. Also, the lactose in the nanocomposites demonstrated higher molecular mobility than that of neat amorphous lactose. This study provides a foundation for understanding functional properties of lactose/Na-MMT nanocomposites, such as loading capacity and physical stability.
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http://dx.doi.org/10.1021/acs.langmuir.6b01967DOI Listing
December 2016

(19) F NMR Spectroscopy as a Highly Sensitive Method for the Direct Monitoring of Confined Crystallization within Nanoporous Materials.

Angew Chem Int Ed Engl 2016 07 7;55(31):8904-8. Epub 2016 Jun 7.

School of Pharmacy, University of East Anglia, Norwich, UK.

The introduction of fluorine into the structure of pharmaceuticals has been an effective strategy for tuning their pharmacodynamic properties, with more than 40 new drugs entering the market in the last 15 years. In this context, (19) F NMR spectroscopy can be viewed as a useful method for investigating the host-guest chemistry of pharmaceuticals in nanosized drug-delivery systems. Although the interest in confined crystallization, nanosized devices, and porous catalysts is gradually increasing, understanding of the complex phase behavior of organic molecules confined within nanochambers or nanoreactors is still lacking. Using (19) F magic-angle-spinning NMR spectroscopy, we obtained detailed mechanistic insight into the crystallization of flufenamic acid (FFA) in a confined environment of mesoporous silica materials with different pore diameters (3.2-29 nm), providing direct experimental evidence for the formation of a molecular-liquid-like layer besides crystalline confined FFA form I.
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http://dx.doi.org/10.1002/anie.201602936DOI Listing
July 2016

Assembly of α-Glucan by GlgE and GlgB in Mycobacteria and Streptomycetes.

Biochemistry 2016 06 2;55(23):3270-84. Epub 2016 Jun 2.

Biological Chemistry Department, John Innes Centre , Norwich Research Park, Norwich NR4 7UH, United Kingdom.

Actinomycetes, such as mycobacteria and streptomycetes, synthesize α-glucan with α-1,4 linkages and α-1,6 branching to help evade immune responses and to store carbon. α-Glucan is thought to resemble glycogen except for having shorter constituent linear chains. However, the fine structure of α-glucan and how it can be defined by the maltosyl transferase GlgE and branching enzyme GlgB were not known. Using a combination of enzymolysis and mass spectrometry, we compared the properties of α-glucan isolated from actinomycetes with polymer synthesized in vitro by GlgE and GlgB. We now propose the following assembly mechanism. Polymer synthesis starts with GlgE and its donor substrate, α-maltose 1-phosphate, yielding a linear oligomer with a degree of polymerization (∼16) sufficient for GlgB to introduce a branch. Branching involves strictly intrachain transfer to generate a C chain (the only constituent chain to retain its reducing end), which now bears an A chain (a nonreducing end terminal branch that does not itself bear a branch). GlgE preferentially extends A chains allowing GlgB to act iteratively to generate new A chains emanating from B chains (nonterminal branches that themselves bear a branch). Although extension and branching occur primarily with A chains, the other chain types are sometimes extended and branched such that some B chains (and possibly C chains) bear more than one branch. This occurs less frequently in α-glucans than in classical glycogens. The very similar properties of cytosolic and capsular α-glucans from Mycobacterium tuberculosis imply GlgE and GlgB are sufficient to synthesize them both.
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http://dx.doi.org/10.1021/acs.biochem.6b00209DOI Listing
June 2016

Physicochemical characterization and dissolution studies of acyclovir solid dispersions with Pluronic F127 prepared by the kneading method.

Acta Pharm 2016 Mar;66(1):119-28

The dissolution rate of anhydrous acyclovir was improved by the preparation of physical mixtures and solid dispersions with the non-ionic polymer Pluronic F127 using the kneading method at different drug-to-polymer ratios. The obtained physical mixtures and solid dispersions were examined in terms of drug content and possible physical and chemical interactions between the drug and polymer using FTIR spectral studies, differential scanning calorimetry and powder X-ray diffraction analysis. The dissolution rate of acyclovir was determined using the rotating disk method. It was found that the minimal content of the polymer within the mixtures needed to increase the dissolution rate of the drug was 50 %.
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http://dx.doi.org/10.1515/acph-2016-0008DOI Listing
March 2016

Structural Properties, Order-Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms.

Mol Pharm 2016 Mar 25;13(3):1012-29. Epub 2016 Jan 25.

Institute of Pharmacy, University of Innsbruck , Innrain 52c, 6020 Innsbruck, Austria.

Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 °C and loses only a small part of the water when stored over desiccants (25 °C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order-disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration.
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http://dx.doi.org/10.1021/acs.molpharmaceut.5b00856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783786PMC
March 2016

Mechanistic and Kinetic Insight into Spontaneous Cocrystallization of Isoniazid and Benzoic Acid.

Mol Pharm 2015 Aug 2;12(8):2981-92. Epub 2015 Jul 2.

‡School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, U.K.

Solid-state cocrystallization is of contemporary interest because it offers an easy and efficient way to produce cocrystals, which are recognized as prospective pharmaceutical materials. Research explaining solid-state cocrystallization mechanisms is important but still too scarce to give a broad understanding of factors governing and limiting these reactions. Here we report an investigation of the mechanism and kinetics of isoniazid cocrystallization with benzoic acid. This reaction is spontaneous; however, its rate is greatly influenced by environmental conditions (humidity and temperature) and pretreatment (milling) of the sample. The acceleration of cocrystallization in the presence of moisture is demonstrated by kinetic studies at elevated humidity. The rate dependence on humidity stems from moisture facilitated rearrangements on the surface of isoniazid crystallites, which lead to cocrystallization in the presence of benzoic acid vapor. Furthermore, premilling the mixture of the cocrystal ingredients eliminated the induction time of the reaction and considerably increased its rate.
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http://dx.doi.org/10.1021/acs.molpharmaceut.5b00250DOI Listing
August 2015

Evaluation of the toxicity of anticancer chemotherapy in patients with colon cancer.

Adv Clin Exp Med 2015 Jan-Feb;24(1):103-11

Department of Clinical Pharmacology, Wroclaw Medical University, Poland.

Background: Modern anticancer chemotherapy can cause numerous adverse effects in the organism, whose functioning has already been disrupted by the neoplastic process itself.

Objectives: The aim of the study was to evaluate and compare the frequency and severity of the toxicity of FOLFOX-4 and CLF-1 anticancer therapy in patients with colon cancer, and to analyze certain factors that might have increased the toxicity of the chemotherapy.

Material And Methods: The study involved 64 patients suffering from generalized colon cancer, including 48 patients treated according to the FOLFOX-4 regimen and 16 patients treated according to the CLF-1 regimen. The toxicity of each regimen was analyzed on the basis of a confidential questionnaire formulated by the authors and laboratory research according to the extended WHO toxicity criteria.

Results: The analysis of the symptoms of toxicity symptoms associated with the use of the FOLFOX-4 and CLF-1 therapeutic regimens revealed that the most common side effects included nausea and vomiting, despite ondansetron premedication, and neurotoxicity. Disruption of the functioning of the nervous system under the FOLFOX-4 regimen statistically significant exacerbation that increased with the number of chemotherapy cycles administered; this was more common and more severe in women. Paresthesia was also revealed to be a neurotoxic effect of the FOLFOX-4 regimen after termination of therapy. A statistically significant relationship was observed between the use of vitamin supplements and the incidence and severity of the toxicity of the FOLFOX-4 regimen.

Conclusions: The findings of the current study regarding the toxicity of the FOLFOX-4 and CLF-1 therapy regimens should be taken into consideration when monitoring chemotherapy safety in colon cancer. The patients' tolerance of the administered medication and the side effects reported by patients should be constantly evaluated, which will help prevent these side effects, apply appropriate therapy and contribute to the improvement of the patients' quality of life. The functioning of the central nervous system should be carefully evaluated when planning the anticancer therapy, especially if repeated administration of neurotoxic drugs is necessary in cases of a recurrence of the disease. Chemotherapy should be thoroughly monitored for safety, especially in women over 65 years of age suffering from coexisting diseases. Colon cancer patients and their families should be informed of the risks of nutritional supplements before the start of the anticancer chemotherapy, and may need to dispense with their use.
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http://dx.doi.org/10.17219/acem/38154DOI Listing
June 2015

Solid dispersion in pharmaceutical technology. Part II. The methods of analysis of solid dispersions and examples of their application.

Polim Med 2012 ;42(2):97-107

Department of Drug Form Technology, Wroclaw Medical University, Wroclaw, Poland.

In the first part of the article solid dispersions were classified the properties and methods of their preparation were described. This section presents methods of analysis of solid dispersions i.e.: thermoanalytical methods, XRPD, FTIR, microscopic methods, dissolution studies and examples of drug forms where solid dispersions were used.
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October 2012
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