Nanocrystals: An Overview of Fabrication, Characterization and Therapeutic Applications in Drug Delivery.

Approximately 40 % drugs in the market are having poor aqueous solubility related problems and 70 % molecules in discovery pipeline are being practically insoluble in water. Nanocrystals is a prominent tool to solve the issue related to poor aqueous solubility and helps in improving the bioavailability of many drugs as reported in the literature. Nanocrystals can be prepared by top down methods, bottom up methods and combination methods. Many patented products such as Nanocrystals®, DissoCubes®, NANOEDGE® and SmartCrystals ®, etc., are available, which are based on these three preparation methodologies. The particle size reduction resulted into unstable nanocrystalline system and the phenomenon of Ostawald ripening occurs. This instability issue could be resolved by using an appropriate stabilizers or combination of stabilizers. The nanosuspensions could be transformed to the solid state to prevent particle aggregation in liquid state by employing various unit operations such as lyophilisation, spray drying, granulation and pelletisation. These techniques are well known for their scalability and continuous nanocrystal formation advantages. Nanocrystals can be characterized by using scanning electron microscopy, transmission electron microscopy, atomic force microscopy, differential scanning calorimetry, fourier transform infrared spectroscopy, powdered x- ray diffraction and photon correlation spectroscopy. The downscaling of nanocrystals will enable rapid optimization of nanosuspension formulation in parallel screening design of preclinical developmental stage drug moieties. One of the most acceptable advantages of nanocrystals is their wide range of applicability such as oral delivery, ophthalmic delivery, pulmonary delivery, transdermal delivery, intravenous delivery and targeting (brain and tumor targeting). The enhancement in market value of nanocrystals as well as the amount of nanocrystal products in the market is gaining attention to be used as an approach in order to get commercial benefits.

[1]  G. Zhai,et al.  In vivo evaluation of curcumin loaded nanosuspensions by oral administration. , 2012, Journal of biomedical nanotechnology.

[2]  R. Müller,et al.  Production and Characterization of a Budesonide Nanosuspension for Pulmonary Administration , 2002, Pharmaceutical Research.

[3]  Jenni Pessi,et al.  Coated particle assemblies for the concomitant pulmonary administration of budesonide and salbutamol sulphate. , 2013, International journal of pharmaceutics.

[4]  Jouni Hirvonen,et al.  Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods , 2010, The Journal of pharmacy and pharmacology.

[5]  R. Müller,et al.  Adsorption kinetics of plasma proteins on solid lipid nanoparticles for drug targeting. , 2005, International journal of pharmaceutics.

[6]  A. Fahr,et al.  Nano- and micro-particulate formulations of poorly water-soluble drugs by using a novel optimized technique. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[7]  H. Krumholz,et al.  Avoidance of generic competition by Abbott Laboratories' fenofibrate franchise. , 2012, Archives of internal medicine.

[8]  Y. Yeo,et al.  Enhancing Docetaxel Delivery to Multidrug-Resistant Cancer Cells with Albumin-Coated Nanocrystals. , 2018, Molecular pharmaceutics.

[9]  J. Xie,et al.  Apolipoproteins adsorption and brain-targeting evaluation of baicalin nanocrystals modified by combination of Tween80 and TPGS. , 2017, Colloids and surfaces. B, Biointerfaces.

[10]  Jouni Hirvonen,et al.  Stabilizing Agents for Drug Nanocrystals: Effect on Bioavailability , 2016, Pharmaceutics.

[11]  Ying Zheng,et al.  Oral Delivery of a Nanocrystal Formulation of Schisantherin A with Improved Bioavailability and Brain Delivery for the Treatment of Parkinson's Disease. , 2016, Molecular pharmaceutics.

[12]  P. Wei,et al.  Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery , 2011, International journal of nanomedicine.

[13]  R. Müller,et al.  Production and characterization of antioxidant apigenin nanocrystals as a novel UV skin protective formulation. , 2011, International journal of pharmaceutics.

[14]  Filippos Kesisoglou,et al.  Nanosizing--oral formulation development and biopharmaceutical evaluation. , 2007, Advanced drug delivery reviews.

[15]  V. Junyaprasert,et al.  Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs , 2015 .

[16]  Jukka Rantanen,et al.  Budesonide nanocrystal-loaded hyaluronic acid microparticles for inhalation: In vitro and in vivo evaluation. , 2018, Carbohydrate polymers.

[17]  F. Cui,et al.  Preparation of stable nitrendipine nanosuspensions using the precipitation-ultrasonication method for enhancement of dissolution and oral bioavailability. , 2010, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[18]  Khalid Saeed,et al.  Nanoparticles: Properties, applications and toxicities , 2017, Arabian Journal of Chemistry.

[19]  A. Fadda,et al.  Nanosuspension improves tretinoin photostability and delivery to the skin. , 2013, International journal of pharmaceutics.

[20]  Aihua Yu,et al.  Preparation and characterization of intravenously injectable curcumin nanosuspension , 2011, Drug delivery.

[21]  W. Pan,et al.  Bovine serum albumin-meloxicam nanoaggregates laden contact lenses for ophthalmic drug delivery in treatment of postcataract endophthalmitis. , 2014, International journal of pharmaceutics.

[22]  B. Gates,et al.  Synthesis of Lithium Niobate Nanocrystals with Size Focusing through an Ostwald Ripening Process , 2018 .

[23]  Ji-Ho Park,et al.  Endocytosis and exocytosis of nanoparticles in mammalian cells , 2014, International journal of nanomedicine.

[24]  N. Rasenack,et al.  Microcrystals for dissolution rate enhancement of poorly water-soluble drugs. , 2003, International journal of pharmaceutics.

[25]  Julie W. Fitzpatrick,et al.  Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy , 2005, Particle and Fibre Toxicology.

[26]  Honglei Zhan,et al.  A new targeted delivery approach by functionalizing drug nanocrystals through polydopamine coating , 2017, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[27]  R. Tan,et al.  Continuous and scalable process for water-redispersible nanoformulation of poorly aqueous soluble APIs by antisolvent precipitation and spray-drying. , 2011, International journal of pharmaceutics.

[28]  G Vergnault,et al.  Pharmacokinetic evaluation of oral fenofibrate nanosuspensions and SLN in comparison to conventional suspensions of micronized drug. , 2007, Advanced drug delivery reviews.

[29]  Rainer H Müller,et al.  Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[30]  R. Müller,et al.  Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future. , 2001, Advanced drug delivery reviews.

[31]  Qi Chang,et al.  Formulation of 20(S)-protopanaxadiol nanocrystals to improve oral bioavailability and brain delivery. , 2016, International journal of pharmaceutics.

[32]  S. Vaghani,et al.  Itraconazole nanosuspension for oral delivery: Formulation, characterization and in vitro comparison with marketed formulation , 2010, Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences.

[33]  R. Müller,et al.  Kinetic solubility and dissolution velocity of rutin nanocrystals. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[34]  Mengjiao Zhou,et al.  The aspect ratio effect of drug nanocrystals on cellular internalization efficiency, uptake mechanisms, and in vitro and in vivo anticancer efficiencies. , 2015, Nanoscale.

[35]  Jeong-Sook Park,et al.  Development of docetaxel nanocrystals surface modified with transferrin for tumor targeting , 2016, Drug design, development and therapy.

[36]  Rainer H. Müller,et al.  Drug Nanocrystals/Nanosuspensions for the Delivery of Poorly Soluble Drugs , 2006 .

[37]  R. Pignatello,et al.  Eudragit RS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofen. , 2002, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[38]  T. Tan,et al.  Preparation of Azithromycin Nanosuspensions by High Pressure Homogenization and its Physicochemical Characteristics Studies , 2007, Drug development and industrial pharmacy.

[39]  P. Pawar,et al.  Preparation and In Vitro/Ex Vivo Evaluation of Moxifloxacin-Loaded PLGA Nanosuspensions for Ophthalmic Application , 2013, Scientia pharmaceutica.

[40]  F. Liu,et al.  Targeted cancer therapy with novel high drug-loading nanocrystals. , 2010, Journal of pharmaceutical sciences.

[41]  H. Hinrichsen,et al.  Agglomeration of charged nanopowders in suspensions , 2002, cond-mat/0210187.

[42]  R. Müller,et al.  Resveratrol nanosuspensions for dermal application--production, characterization, and physical stability. , 2009, Die Pharmazie.

[43]  Timo Laaksonen,et al.  Nanosuspensions of poorly soluble drugs: preparation and development by wet milling. , 2011, International journal of pharmaceutics.

[44]  Rainer H Müller,et al.  Production and characterization of Hesperetin nanosuspensions for dermal delivery. , 2009, International journal of pharmaceutics.

[45]  G. Pastorin,et al.  Preparation of drug nanocrystals embedded in mannitol microcrystals via liquid antisolvent precipitation followed by immediate (on-line) spray drying , 2018 .

[46]  M. Samanta,et al.  Dual-Drug Delivery System Based on In Situ Gel-Forming Nanosuspension of Forskolin to Enhance Antiglaucoma Efficacy , 2010, AAPS PharmSciTech.

[47]  D. Mathieu,et al.  Development of 5-iodo-2'-deoxyuridine milling process to reduce initial burst release from PLGA microparticles. , 1999, International journal of pharmaceutics.

[48]  K. Amighi,et al.  Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine. , 2005, International journal of pharmaceutics.

[49]  P. Liu,et al.  Brinzolamide nanocrystal formulations for ophthalmic delivery: reduction of elevated intraocular pressure in vivo. , 2014, International journal of pharmaceutics.

[50]  M. Misra,et al.  Nanocrystal-based drug delivery system of risperidone: lyophilization and characterization , 2018, Drug development and industrial pharmacy.

[51]  Huixia Lv,et al.  Enhanced bioavailability after oral and pulmonary administration of baicalein nanocrystal. , 2011, International journal of pharmaceutics.

[52]  Fang Wang,et al.  Application of Drug Nanocrystal Technologies on Oral Drug Delivery of Poorly Soluble Drugs , 2012, Pharmaceutical Research.

[53]  P. Gassmann,et al.  Hydrosols : alternatives for the parenteral application of poorly water soluble drugs , 1994 .

[54]  C Olbrich,et al.  Formulation of amphotericin B as nanosuspension for oral administration. , 2003, International journal of pharmaceutics.

[55]  R. Censi,et al.  Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs , 2015, Molecules.

[56]  Ying Zheng,et al.  Curcumin Acetate Nanocrystals for sustained Pulmonary Delivery: Preparation, Characterization and In Vivo Evaluation. , 2017, Journal of biomedical nanotechnology.

[57]  S. Honary,et al.  Effect of Zeta Potential on the Properties of Nano-Drug Delivery Systems - A Review (Part 2) , 2013 .

[58]  W. Shi,et al.  The biological characteristics and pharmacodynamics of a mycophenolate mofetil nanosuspension ophthalmic delivery system in rabbits. , 2011, Journal of pharmaceutical sciences.

[59]  N. Blagden,et al.  Hydrocortisone nanosuspensions for ophthalmic delivery: A comparative study between microfluidic nanoprecipitation and wet milling. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[60]  Jeong-Sook Park,et al.  Development and evaluation of targeting ligands surface modified paclitaxel nanocrystals. , 2017, Materials science & engineering. C, Materials for biological applications.

[61]  Ranjita Shegokar,et al.  Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. , 2010, International journal of pharmaceutics.

[62]  Jianfeng Chen,et al.  Preparation of amorphous cefuroxime axetil nanoparticles by controlled nanoprecipitation method without surfactants. , 2006, International journal of pharmaceutics.

[63]  Patrick Augustijns,et al.  Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. , 2008, International journal of pharmaceutics.

[64]  Kale Mohana Raghava Srivalli,et al.  Drug nanocrystals: four basic prerequisites for formulation development and scale-up. , 2015, Current drug targets.

[65]  Lulu Wang,et al.  Nanosuspensions of poorly water-soluble drugs prepared by bottom-up technologies. , 2015, International journal of pharmaceutics.

[66]  J. Zhao,et al.  Nanocrystals embedded in chitosan‐based respirable swellable microparticles as dry powder for sustained pulmonary drug delivery , 2017, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[67]  Vandana B. Patravale,et al.  Current strategies for engineering drug nanoparticles , 2004 .

[68]  Qiang Zhang,et al.  In vitro and in vivo antitumor activity of oridonin nanosuspension. , 2009, International journal of pharmaceutics.

[69]  R. Müller,et al.  Development of ascorbyl palmitate nanocrystals applying the nanosuspension technology. , 2008, International journal of pharmaceutics.

[70]  R. Pignatello,et al.  Preparation and characterization of Eudragit Retard nanosuspensions for the ocular delivery of cloricromene , 2006, AAPS PharmSciTech.

[71]  Yongjun Wang,et al.  Enhanced bioavailability of rebamipide nanocrystal tablets: Formulation and in vitro/in vivo evaluation , 2015 .

[72]  Sanjay Garg,et al.  Formulation and pharmacokinetic evaluation of an asulacrine nanocrystalline suspension for intravenous delivery. , 2009, International journal of pharmaceutics.

[73]  J. Carvalho,et al.  An Overview of Particulate Matter Measurement Instruments , 2015, ATMOS 2015.

[74]  R. Müller,et al.  Dermal miconazole nitrate nanocrystals - formulation development, increased antifungal efficacy & skin penetration. , 2017, International journal of pharmaceutics.

[75]  T. Viitala,et al.  Interaction Studies Between Indomethacin Nanocrystals and PEO/PPO Copolymer Stabilizers , 2015, Pharmaceutical Research.

[76]  R. Müller,et al.  Development of cationic nanocrystals for ocular delivery. , 2016, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[77]  Dianrui Zhang,et al.  Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug delivery system , 2008 .

[78]  J. Pardeike,et al.  Dermal and ocular safety of the new phospholipase A2 inhibitors PX-18 and PX-13 formulated as drug nanosuspension. , 2009, Journal of biomedical nanotechnology.

[79]  Lei Dong,et al.  Preparation and characterization of solid lipid nanoparticles loaded traditional Chinese medicine. , 2006, International journal of biological macromolecules.

[80]  Parikshit Banerjee,et al.  Comparative study on stabilizing ability of food protein, non‐ionic surfactant and anionic surfactant on BCS type II drug carvedilol loaded nanosuspension: Physicochemical and pharmacokinetic investigation , 2017, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[81]  Ying Zheng,et al.  Stability of nanosuspensions in drug delivery. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[82]  Cornelia M Keck,et al.  Challenges and solutions for the delivery of biotech drugs--a review of drug nanocrystal technology and lipid nanoparticles. , 2004, Journal of biotechnology.

[83]  T. Mehta,et al.  Nanocrystal: a novel approach to overcome skin barriers for improved topical drug delivery , 2018, Expert opinion on drug delivery.

[84]  R. Müller,et al.  Lutein nanocrystals as antioxidant formulation for oral and dermal delivery. , 2011, International journal of pharmaceutics.