Influence of mannitol concentration on the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol.

Mannitol is a pharmaceutical excipient that is receiving increased popularity in solid dosage forms. The aim of this study was to provide comparative evaluation on the effect of mannitol concentration on the physicochemical, mechanical, and pharmaceutical properties of lyophilised mannitol. The results showed that the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol powders are strong functions of mannitol concentration. By decreasing mannitol concentration, the true density, bulk density, cohesivity, flowability, netcharge-to-mass ratio, and relative degree of crystallinity of LM were decreased, whereas the breakability, size distribution, and size homogeneity of lyophilised mannitol particles were increased. The mechanical properties of lyophilised mannitol tablets improved with decreasing mannitol concentration. The use of lyophilised mannitol has profoundly improved the dissolution rate of indomethacin from tablets in comparison to commercial mannitol. This improvement exhibited an increasing trend with decreasing mannitol concentration. In conclusion, mannitols lyophilised from lower concentrations are more desirable in tableting than mannitols from higher concentrations due to their better mechanical and dissolution properties.

[1]  A. Zumbe,et al.  Polyols in confectionery: the route to sugar-free, reduced sugar and reduced calorie confectionery. , 2001, The British journal of nutrition.

[2]  R. Suryanarayanan,et al.  Crystallization of D-Mannitol in Binary Mixtures with NaCl: Phase Diagram and Polymorphism , 2003, Pharmaceutical Research.

[3]  Waseem Kaialy,et al.  A review of factors affecting electrostatic charging of pharmaceuticals and adhesive mixtures for inhalation. , 2016, International journal of pharmaceutics.

[4]  Waseem Kaialy,et al.  Recent advances in the engineering of nanosized active pharmaceutical ingredients: Promises and challenges. , 2016, Advances in colloid and interface science.

[5]  Wenjin Cao,et al.  Differentiation and quantitative determination of surface and hydrate water in lyophilized mannitol using NIR spectroscopy. , 2006, Journal of pharmaceutical sciences.

[6]  J. Carpenter,et al.  The ice nucleation temperature determines the primary drying rate of lyophilization for samples frozen on a temperature-controlled shelf. , 2001, Journal of pharmaceutical sciences.

[7]  许旱峤,et al.  Kirk-Othmer Encyclopedia of Chemical Technology数据库介绍及实例 , 2007 .

[8]  Kimio Kawakita,et al.  Some considerations on powder compression equations , 1971 .

[9]  S. Bharate,et al.  Incompatibilities of Pharmaceutical Excipients with Active Pharmaceutical Ingredients: A Comprehensive Review , 2010 .

[10]  G. A. Jeffrey,et al.  The crystal structure of the K form of d‐mannitol , 1968 .

[11]  Waseem Kaialy,et al.  An approach to engineer paracetamol crystals by antisolvent crystallization technique in presence of various additives for direct compression. , 2014, International journal of pharmaceutics.

[12]  R. Bruttini,et al.  Heating Policies during the Primary and Secondary Drying Stages of the Lyophilization Process in Vials: Effects of the Arrangement of Vials in Clusters of Square and Hexagonal Arrays on Trays , 2004 .

[13]  J. Yliruusi,et al.  Pore structure and surface area of mannitol powder, granules and tablets determined with mercury porosimetry and nitrogen adsorption. , 1998, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[14]  S. Nail,et al.  The physical state of mannitol after freeze-drying: effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute. , 1998, Journal of pharmaceutical sciences.

[15]  George Zografi,et al.  The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state , 1990 .

[16]  Keith P. Johnston,et al.  Enhanced Aqueous Dissolution of a Poorly Water Soluble Drug by Novel Particle Engineering Technology: Spray-Freezing into Liquid with Atmospheric Freeze-Drying , 2003, Pharmaceutical Research.

[17]  Davide Fissore,et al.  Freeze Drying of Pharmaceutical Excipients Close to Collapse Temperature: Influence of the Process Conditions on Process Time and Product Quality , 2009 .

[18]  Julien Andrieu,et al.  Effect of ultrasound-controlled nucleation on structural and morphological properties of freeze-dried mannitol solutions , 2008 .

[19]  Don W. Green,et al.  Perry's Chemical Engineers' Handbook , 2007 .

[20]  N. Rasenack,et al.  Micron‐Size Drug Particles: Common and Novel Micronization Techniques , 2004, Pharmaceutical development and technology.

[21]  Heribert Häusler,et al.  Influence of mechanical activation on the physical stability of salbutamol sulphate. , 2003, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[22]  J. Newton,et al.  Determination of tablet strength by the diametral-compression test. , 1970, Journal of pharmaceutical sciences.

[23]  R. Suryanarayanan,et al.  Crystallization Behavior of Mannitol in Frozen Aqueous Solutions , 2004, Pharmaceutical Research.

[24]  Julien Andrieu,et al.  A Direct Characterization Method of the Ice Morphology. Relationship Between Mean Crystals Size and Primary Drying Times of Freeze-Drying Processes , 2004 .

[25]  P. Schmidt,et al.  Investigations on polymorphism of mannitol/ sorbitol mixtures after spray-drying using Differential scanning calorimetry, X-ray diffraction and Near-Infrared spectroscopy , 2000 .

[26]  Waseem Kaialy,et al.  The enhanced aerosol performance of salbutamol from dry powders containing engineered mannitol as excipient. , 2010, International journal of pharmaceutics.

[27]  Stanley E. Charm,et al.  Freeze Drying , 1964 .

[28]  Waseem Kaialy,et al.  Dry powder inhalers: physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol. , 2015, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[29]  F. Rodolphe,et al.  Vacuum freeze-drying of a liquid in a vial: determination of heat and mass-transfer coefficients and optimisation of operating pressure , 1993 .

[30]  Amelia Carolina Sparavigna,et al.  Freeze-drying of enzymes in case of water-binding and non-water-binding substrates. , 2013, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[31]  C Vervaet,et al.  Implementation of a process analytical technology system in a freeze-drying process using Raman spectroscopy for in-line process monitoring. , 2007, Analytical chemistry.

[32]  S. Yoshioka,et al.  Effect of mannitol crystallinity on the stabilization of enzymes during freeze-drying. , 1994, Chemical & pharmaceutical bulletin.

[33]  Eva Schornick,et al.  Why is mannitol becoming more and more popular as a pharmaceutical excipient in solid dosage forms? , 2014, Pharmaceutical development and technology.

[34]  K. A. Khan The concept of dissolution efficiency , 1975, The Journal of pharmacy and pharmacology.

[35]  Xiaolin Tang,et al.  Design of Freeze-Drying Processes for Pharmaceuticals: Practical Advice , 2004, Pharmaceutical Research.

[36]  D. Stichtenoth,et al.  [Lactose-containing tablets for patients with lactose intolerance?]. , 2009, Medizinische Monatsschrift fur Pharmazeuten.

[37]  G. Amidon,et al.  Protein denaturation during freezing and thawing in phosphate buffer systems: monomeric and tetrameric beta-galactosidase. , 2000, Archives of biochemistry and biophysics.

[38]  G. P. Martin,et al.  The Influence of Crystallization Conditions on the Morphology of Lactose Intended for Use as a Carrier for Dry Powder Aerosols , 2000, The Journal of pharmacy and pharmacology.

[39]  M. Pikal,et al.  High-precision absolute (true) density measurements on hygroscopic powders by gas pycnometry: application to determining effects of formulation and process on free volume of lyophilized products. , 2011, Journal of pharmaceutical sciences.

[40]  D. Mishra,et al.  Existence of a mannitol hydrate during freeze-drying and practical implications. , 1999, Journal of pharmaceutical sciences.

[41]  H. Tong,et al.  Control of Physical Forms of Drug Particles for Pulmonary Delivery by Spray Drying and Supercritical Fluid Processing , 2007 .

[42]  J. Rollinger,et al.  Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol. , 2000, Journal of pharmaceutical sciences.

[43]  A. J. Cannon,et al.  The influence of lyophilization on the polymorphic behavior of mannitol. , 2000, PDA journal of pharmaceutical science and technology.

[44]  H. Larhrib,et al.  Influence of Batch Cooling Crystallization on Mannitol Physical Properties and Drug Dispersion from Dry Powder Inhalers , 2012 .

[45]  Felix Franks,et al.  Freeze-drying of Pharmaceuticals and Biopharmaceuticals , 2007 .

[46]  Antonello Barresi,et al.  Development of simplified models for the freeze-drying process and investigation of the optimal operating conditions , 2008 .

[47]  S. Olson,et al.  Particle damage observed in ring shear tests on sands , 2010 .

[48]  Peter York,et al.  The improved compaction properties of mannitol after a moisture-induced polymorphic transition. , 2003, International journal of pharmaceutics.

[49]  R. Suryanarayanan,et al.  Crystal structure of anhydrous δ-D-mannitol , 2003, Powder Diffraction.

[50]  R. Suryanarayanan,et al.  Influence of Processing Conditions on the Physical State of Mannitol—Implications in Freeze-Drying , 2007, Pharmaceutical Research.

[51]  H. Steckel,et al.  Effect of milling and sieving on functionality of dry powder inhalation products. , 2006, International journal of pharmaceutics.

[52]  M. Bradley,et al.  Evaluation studies of a sensing technique for electrostatic charge polarity of pharmaceutical particulates , 2016 .

[53]  Wiel H. Janssen,et al.  Evaluation studies , 1993, Generic Intelligent Driver Support.

[54]  Reinhard Vehring,et al.  Pharmaceutical Particle Engineering via Spray Drying , 2007, Pharmaceutical Research.

[55]  Waseem Kaialy,et al.  A novel sensing technique for measurement of magnitude and polarity of electrostatic charge distribution across individual particles. , 2013, International journal of pharmaceutics.

[56]  C Vervaet,et al.  In-line and real-time process monitoring of a freeze drying process using Raman and NIR spectroscopy as complementary process analytical technology (PAT) tools. , 2009, Journal of pharmaceutical sciences.

[57]  F. Franks Freeze-Drying/Lyophilisation of Pharmaceutical and Biological Products , 2000 .

[58]  R. Suryanarayanan,et al.  Characterization of phase transitions during freeze-drying by in situ X-ray powder diffractometry. , 1998, Pharmaceutical development and technology.

[59]  Roberto Pisano,et al.  Impact of vacuum-induced surface freezing on inter- and intra-vial heterogeneity. , 2016, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[60]  Julien Andrieu,et al.  Influence of controlled nucleation by ultrasounds on ice morphology of frozen formulations for pharmaceutical proteins freeze-drying , 2006 .

[61]  P York,et al.  Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. , 2007, Advanced drug delivery reviews.

[62]  Håkan Wikström,et al.  Monitoring of mannitol phase behavior during freeze-drying using non-invasive Raman spectroscopy. , 2007, PDA journal of pharmaceutical science and technology.

[63]  Ingo Heschel,et al.  The influence of the freezing process on vapour transport during sublimation in vacuum-freeze-drying of macroscopic samples , 1993 .

[64]  G. A. Jeffrey,et al.  The crystal structures of the a' and forms of D-mannitol , 1968 .

[65]  A. Campbell,et al.  Quantifying the ‘hidden’ lactose in drugs used for the treatment of gastrointestinal conditions , 2009, Alimentary pharmacology & therapeutics.

[66]  R. Suryanarayanan,et al.  Characterization and crystal structure of D-mannitol hemihydrate. , 2004, Journal of pharmaceutical sciences.