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UNCORRECTED PROOF 1 Review 2 Engineered nanocrystal technology: In-vivo fate, targeting and 3 applications in drug delivery Vivek K. Q1 Pawar, Yuvraj Singh, Jaya Gopal Meher, Siddharth Gupta, Manish K. Chourasia 5 Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, India abstract 6 article info 7 Article history: 8 Received 23 January 2014 9 Accepted 17 March 2014 10 Available online xxxx 11 Keywords: 12 Nanocrystals 13 Poorly soluble drugs 14 In-vivo fate 15 Bioavailability 16 Stability 17 Targeted delivery 18 Formulation of nanocrystals is a robust approach which can improve delivery of poorly water soluble drugs, a 19 challenge pharmaceutical industry has been facing since long. Large scale production of nanocrystals is done 20 by techniques like precipitation, media milling and, high pressure homogenization. Application of stabilizers 21 along with drying is in accord with nanocrystals' long term stability and commercial viability Q2 . These can be 22 administered through oral, parenteral, pulmonary, dermal and ocular routes showing their high therapeutic 23 applicability. They serve to target drug molecules in specic regions through size manipulation and surface 24 modication. This review dwells upon the in-vivo fate and varying applications in addition to the facets of drug 25 nanocrystals stated above. 26 © 2014 Published by Elsevier B.V. 27 28 29 30 31 32 Contents 33 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 34 2. Fabrication technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 35 2.1. Bottom-up technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 36 2.2. Top-down technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 37 2.3. Combination technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 38 3. Nanocrystal stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 39 3.1. Poloxamers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 40 3.2. Polyvinyl pyrrolidone (PVP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 41 3.3. Polyvinyl alcohol (PVA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 42 3.4. Amino acid derived co-polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 43 3.5. Brij-78 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 44 3.6. Lecithin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 45 3.7. D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS/TPGS 1000) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 46 3.8. Polysorbate 80 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 47 3.9. Sodium lauryl sulphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 48 3.10. HPMC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 49 3.11. Sodium cholic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 50 4. Ensuring long term stability: drying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 51 5. Fate of nanocrystals in biological environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 52 6. Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 53 6.1. Oral drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 54 6.2. Intravenous drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 55 6.3. Pulmonary drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 56 6.4. Ocular drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 57 6.5. Dermal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Journal of Controlled Release xxx (2014) xxxxxx Corresponding author at: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India. Tel.: +91 522 2612411 18; fax: +91 522 2623405. E-mail address: [email protected] (M.K. Chourasia). COREL-07087; No of Pages 16 http://dx.doi.org/10.1016/j.jconrel.2014.03.030 0168-3659/© 2014 Published by Elsevier B.V. Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel Please cite this article as: V.K. Pawar, et al., Engineered nanocrystal technology: In-vivo fate, targeting and applications in drug delivery, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.03.030
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Journal of Controlled Release xxx (2014) xxx–xxx

COREL-07087; No of Pages 16

Contents lists available at ScienceDirect

Journal of Controlled Release

j ourna l homepage: www.e lsev ie r .com/ locate / jconre l

Review

Engineered nanocrystal technology: In-vivo fate, targeting andapplications in drug delivery

FVivek K. Pawar, Yuvraj Singh, Jaya Gopal Meher, Siddharth Gupta, Manish K. Chourasia ⁎Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, India

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⁎ Corresponding author at: Pharmaceutics Division, CSIE-mail address: [email protected] (M.K. C

http://dx.doi.org/10.1016/j.jconrel.2014.03.0300168-3659/© 2014 Published by Elsevier B.V.

Please cite this article as: V.K. Pawar, et al., EnRelease (2014), http://dx.doi.org/10.1016/j.j

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Article history:Received 23 January 2014Accepted 17 March 2014Available online xxxx

Keywords:NanocrystalsPoorly soluble drugsIn-vivo fateBioavailabilityStabilityTargeted delivery

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Formulation of nanocrystals is a robust approach which can improve delivery of poorly water soluble drugs, achallenge pharmaceutical industry has been facing since long. Large scale production of nanocrystals is doneby techniques like precipitation, media milling and, high pressure homogenization. Application of stabilizersalong with drying is in accord with nanocrystals' long term stability and commercial viability. These can beadministered through oral, parenteral, pulmonary, dermal and ocular routes showing their high therapeuticapplicability. They serve to target drug molecules in specific regions through size manipulation and surfacemodification. This review dwells upon the in-vivo fate and varying applications in addition to the facets of drugnanocrystals stated above.

© 2014 Published by Elsevier B.V.

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Contents

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1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02. Fabrication technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2.1. Bottom-up technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.2. Top-down technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.3. Combination technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

3. Nanocrystal stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.1. Poloxamers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.2. Polyvinyl pyrrolidone (PVP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.3. Polyvinyl alcohol (PVA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.4. Amino acid derived co-polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.5. Brij-78 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.6. Lecithin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.7. D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS/TPGS 1000) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.8. Polysorbate 80 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.9. Sodium lauryl sulphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.10. HPMC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.11. Sodium cholic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

4. Ensuring long term stability: drying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05. Fate of nanocrystals in biological environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 06. Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

6.1. Oral drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 06.2. Intravenous drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 06.3. Pulmonary drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 06.4. Ocular drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 06.5. Dermal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

R-Central Drug Research Institute, Lucknow, UP 226031, India. Tel.: +91 522 2612411 18; fax: +91 522 2623405.hourasia).

gineered nanocrystal technology: In-vivo fate, targeting and applications in drug delivery, J. Control.conrel.2014.03.030

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7. Targeted nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 08. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

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1. Introduction

With the advancement of drug delivery technology, use of engineerednanoparticles has revolutionised the diagnosis and treatment of diseaseby targeting drugs to various cellular sites. Previously, attaining such aselective delivery and reduced dose dependent toxicity (especially incase of anticancer drugs) with conventional methods was merely adream [1]. Almost 70% of the newly researched molecules are facing is-sues of poor aqueous solubility which finally leads to poor bioavailability[2]. Many strategies have been adopted to overcome this problem likesurfactant utilization [3], inclusion complexation [4], co-solvency [5],and solid dispersion [6], and emphasis is being laid on preparation ofsafe and effective dosage forms with better bioavailability. Reduction ofparticle size to nano-metric region is also being applied to achieve thesame. Governed byNoyes–Whitney theory, smaller particleswith greatersurface to volume ratio (Fig. 1) effectively increase the dissolution rate ofactive ingredients by raising their saturation solubility [7,8]. Nanocrystalscan follow the abovementioned criteria because they are developed in acrystalline state which has particle size in nano-scale [9–11]. Thus,nanocrystals enhance the bioavailability of drugs that undergo erraticabsorption [12–14]. They do not involve use of extreme pH ranges forsolubilisation, due to which it is possible to reduce the solvent relatedadverse effects. Another distinct advantage of nanocrystals is their capa-bility to offer almost 100% drug content which raises the probability ofobtaining higher therapeutic concentration producing desired pharmaco-logical action [15] and makes them superior to other colloidal drugdelivery systems (Fig. 2). They can be administered through variousroutes including parenteral [16], ocular [17], oral [18] and pulmonary[19] which make them extremely versatile.

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Fig. 1. Artistic impression depicting higher dissolution rates linked with particle sizereduction. Intuitively, associating smaller sized particles to larger surface area is difficultto comprehend. But as is self explanatory from the diagram which employs cube as amodel drug crystal, conversion into nanocrystals raises the surface area massively forthe same volume of drug. Exposition of new surface area (pink coloured) as a result ofreduced particle size is available for drug dissolution. This mechanism plays dominantrole in raising the intrinsic solubility ofmanywater incompliant drugs. (For interpretationof the references to colour in this figure legend, the reader is referred to theweb version ofthis article.)

Please cite this article as: V.K. Pawar, et al., Engineered nanocrystal technolRelease (2014), http://dx.doi.org/10.1016/j.jconrel.2014.03.030

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Thorough investigations on nanocrystals have been carried out inthe past 10–15 years which led to development of many marketedproducts (Table 1). Various production technologies have been broughtin use for the development of these nanocrystals which can besummarised as: bottom-up (precipitation), top-down (media millingand high pressure homogenization), combination approaches andchemical synthesis. Additionally, during the developmental journey ofnanocrystals certain modifications are implemented for obtainingdesired properties. High industrial scalability of production methodssuggests that long unfulfilled potential held by therapeutic nanotech-nology has been duly realized by nanocrystals [20].

Considering the prospects and industrial consequences of nano-crystals, an effort has been made to summarize different strategiesused for formulating nanocrystals and challenging issues in their longterm stability. Furthermore, hypothesis/postulate expounding “in-vivofate of nanocrystals” aided with corresponding experimental findingssubstantiating these claims has also been brought forward. Currentperspective ends with detailed introspection into targeting potentialof nanocrystals in biological systems along with their versatile applica-tions in drug delivery.

2. Fabrication technologies

Bulk of nanocrystals is made up of drug itself with nominal utili-zation of excipients like surface stabilizing agents. Simplisticmanufacturing technology and low ingredient requirement reducethe overall cost of production making the process easy for scale-up.They can also be sterilized easily with conventional methods includingheat/steam/radiation sterilization. Scientists have explored various con-sequences of sterilizing nanocrystals and come up with a completelysterile and healthy facility for producing nanocrystals of cytotoxicdrugs [21,22]. Bottom-up and top-down technologies are the twobasic approaches for the production of nanocrystals and a combinationof these two technologies is often sufficient to induce size reduction inmost of the cases (Fig. 3).

2.1. Bottom-up technologies

Also termed as nanoprecipitation, bottom-up techniquewas first in-troduced by List and Sucker [23]. This technique involves solubilisationof drug in a suitable solvent followed by precipitation of dissolved drugvia adding a non-solvent which results into production of nanocrystals[24]. However, most of the modern therapeutic entities are not easilysoluble in common organic solventswhich themselves are toxic and dif-ficult to completely remove thus limiting the applicability of themethod[25].With expense of time, advancement in technologies has led to pro-duction of nanocrystals using various supercritical fluid technologies.These technologies involve gas anti-solvent recrystallization (GAS),aerosol solvent ex-traction system (ASES) [26], atomised rapid injectionfor solvent extraction (ARISE), rapid expansion of supercritical solution(RESS) [27] and depressurization of an expanded liquid organic solution(DELOS) [28].

2.2. Top-down technologies

These technologies employ a high force for diminution of particlesize and can be applied to a wide range of insoluble ‘brick dust drugs’that generally face solubility issues. A traditional top-down technologyusually produces nano-size crystals by milling a drug. Initially, jet

ogy: In-vivo fate, targeting and applications in drug delivery, J. Control.

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Q19 Fig. 2. Structural arrangement of (A) nanoparticles, (B) nanoemulsions, (C) liposomes and (D) nanocrystals with emphasis on drug distribution. Nanocrystals are unique as the drug itselfmakes the bulk of the carrier unlike other colloidal carrierswhich consist of drug dispersed or entrapped in release rate controlling layer. Excipients employed in formulating nanocrystalsprovide them with additional stability and/or targeting properties with limited role in drug release. Shape and size of nanocrystals have special relevance in predicting their functionaloutcome.

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milling was used for particle size reduction but was overtaken by wetmilling because it offers better possibilities for attaining nanonization.Wet milling is a classical technology that involves a media millingchamber, a dispersion medium usually water and a suitable stabilizerto achieve reduction of particle size. Wet milling utilizes both highand low energy processes depending upon the nature of particles.Pearl mill also called Nanocrystal™ technology is a low energy millingprocess and has produced many nano-sized commercial products(Rapamune, Emend®, Tricor® and Megase ES®) [24]. Simultaneously,a Canadian company RTP developed a high energy process, called ashigh pressure homogenization, with the use of a microfluidizer whichworks on the principle of collision and cavitation. Later, this technologywas taken up by SkyePharma PLC, London, UK. Based on the sameprincipal, a technology, named Cubes®, was developed by Muller andco-workers. They utilized piston gap homogenizer for size reduction.With progression in the field of formulation technology, changes werebrought to the classical approaches by partial or full replacement ofwater as suspending media with oil, polyethylene glycol (PEG) orglycerol. This change wasmade by Pharmasol (Berlin, Germany) duringthe development phase of Nanopure® technologywhich allowed directfilling of nano-formulations into capsules or injectables [29].

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2.3. Combination technologies

The specific advantages of the abovementioned technologies wereamalgamated by Baxter (Baxter Pharmaceutical Solutions, LLC, US) inthe form of NANOEDGE™ which introduced a pre-treatment stepwhere the crystals are precipitated to produce a suspension followedby high pressure homogenization. Baxter has modified these technolo-gies to formulate an injectable drug delivery system for poorly solubledrugs which remain stable but product launching in the market stillremains farfetched [7]. However, literature is loaded with exampleswhere combinational technologies have produced stabilized nano-crystals [30–33].

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Table 1Marketed products formulated using drug nanocrystal technology in healthcare.

Product/company Active ingredient Indication

Invega Sustenna/J&Ja Paliperidone palmitate AntideprMegace®ES/Par Pharma Megesterol acetate AppetiteCesamet®/Lilly Nabilone Anti-emeTricor®/Abbott Fenofibrate HyperchoEmend®/Merck Aprepitant Anti-emeRapamune®/Wyeth Sirolimus Immunos

a J&J—Johnson & Johnson.b HPH—High Pressure Homogenization.

Please cite this article as: V.K. Pawar, et al., Engineered nanocrystal technolRelease (2014), http://dx.doi.org/10.1016/j.jconrel.2014.03.030

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O3. Nanocrystal stabilization

Despite, offering an impressive array of advantages, the small size ofnanocrystals can often lead to stability concerns. The massive surfacearea of nanocrystals results in sufficiently high free energy or surfacecharge that might cause attraction or agglomeration [34]. Small sizednanocrystals sometimes raise the solubility of drug beyond the satura-tion point which promotes recrystallization into larger particles; alsoknown as Ostwald ripening. These processes ultimately lead to irrevers-ible loss of formulation integrity.

The simplest indicator of instability associated with nanocrystals isparticle size growth. Increment can be monitored by differential lightscattering method under different sets of conditions. Various advancedanalytical techniques such as X-RD, DSC, NMR and FT-IR are alsoemployed to judge the stability of nanocrystals [18,35]. In addition toformulation behaviour during shelf life, detailed investigations shouldbe carried out to validate the in-vivo stability profile of nanocrystals.For instance nanocrystals intended for oral delivery must be capableof withstanding the harsh gastrointestinal environment. Likewise, par-enterals are subjected to testing in physiological fluids. Furthermore,nanocrystals of water insoluble drugs are always susceptible to precip-itation upon dilution by gastric and other body fluids after administra-tion into the body [36].

Formulation based approaches have been adopted to check such in-stabilities. Ostwald ripening can be negated by employing a suspendingmedia in which the bioactive is extremely insoluble. Agglomeration ofnanocrystals can be curtailed by surface stabilization using a suitableamphiphilic stabilizer having both hydrophilic and hydrophobicdomains in a single functional molecule. The hydrophilic group issuitable for increasing the solubility of poorly soluble drug whereasthe hydrophobic group is in accord with improved stability to thesuspended particles in the dispersion medium [37]. A study demon-strated that hydrophilic compounds having very low enthalpy valueare less suitable stabilizer for development of nanocrystals and theirchoice is dependent upon the hydrophobicity of the subjected drug

Method of preparation Route

essant Top-down, HPHb Parenteralstimulant Top-down, HPHb Oraltic Bottom-up, co-precipitation Orallesterolemia Top-down, media milling Oraltic Top-down, media milling Oraluppressant Top-down, media milling Oral

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Fig. 3.Manufacturing techniques employed towards fabricating nanocrystals. Top-downmethods process primary drug dispersions and scale down the size of drug particles by milling,cavitation, grinding, impaction, shearing, and attrition. Bottom-up techniques work on the principle of nanoprecipitation in which drug solution is introduced in a non-solvent system toinitiate nucleation followed by size growth towards adequate size. Stabilizers are often incorporated in formulation mixture to prevent size fluctuation. A combination of these twotraditional methods can also be applied to manufacture nanocrystals.

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molecule [38]. Some of the excipients used for stabilization of nano-crystals are summarised below:

3.1. Poloxamers

Poloxamers are amphiphilic block copolymers formed with acombination of ethylene oxide (E; hydrophilic) and propyleneoxide (P; hydrophobic) units arranged in an E–P–E arrangement.Poloxamers are available in various grades developed using differentlengths of polymer blocks. They exhibit versatile range of applications indrug delivery due their multiple effects including solubility alteration,stability impartment, and reduction in protein binding. They not onlyserve as ideal stabilizers but also presume the capacity to chemosensitizethe multiple drug resistance (MDR) cells [39–41]. Poloxamers are certi-fied as generally recognized as safe (GRAS) excipient and considerablycause negligible haemolytic reaction hence they are popular for deliveryof drugs through intravenous route [42]. They have beenwidely used forthe stabilization of nanocrystals [43–45].

Poloxamer F188 appended omeprazole nanocrystals showed en-hanced stability due to shielding of the compound and on comparisonwith omeprazole solution, they demonstrated no discoloration in sodi-um bicarbonate solution [46]. A better stability approach has also been

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made by Ganta et al. during the formulation of ascularine nanocrystalswhere the hydrophobic core of the polymer held the molecules stableby binding onto the particle surface [47]. Similarly, tarazepide, a poorlysoluble CCKa-antagonist, was nanomerized using a combination ofpoloxamer 188with polysorbate 80 and glycerol. The developed formu-lations remained unchanged over a period of three months however itwas seen that glycerol only had a trivial role in stabilizing tarazepidenanocrystals [48]. Owing to its ideal combination with polysorbate 80,nanocrystal formulations bearing amphotericin B [49] and loviride [50]were developed. Rabinow et al. developed itraconazole nanocrystalsusing poloxamer 188 and described their role in favourable manipula-tion of pharmacokinetics with decreased Cmax and increased Tmax [51].Mishra et al., fabricated hesperetin nanocrystals for dermal applicationby employing four different stabilizers (poloxamer 188, polysorbate80, Inutec SP1 and decyl glucoside) and they observed that poloxamer188 wasmore efficient in preserving the size of developed nanocrystals[52].

Various researchers have also utilized poloxamer 407 for thedevelopment of several nanocrystal formulations. Deng et al.,attempted to improve the therapeutic profile of paclitaxel by stabilizingits nanocrystals using poloxamer 407, but failed, and ended up withthermo-sensitive miceller structure. However, renanonization with

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incubation sonication led to formation of nanocrystals with prolongedstability [40].

3.2. Polyvinyl pyrrolidone (PVP)

PVP or povidone is prepared by reaction of acetylene and pyrrol-idone to form vinyl pyrrolidone followed by polymerization to convertinto PVP. It is available in different viscosity grades having a versatilerange of application frombeing a binder in tablets and capsules,film for-mers in ophthalmic solution, taste masking agent, toxicity reducer andthe most important as a stabilizer in suspensions.

PVP K30 has been applied as a stabilizer for formation of celecoxibnanocrystals. Two nano-formulations were made; one stabilized witha combination of PVP K30 with sodium dodecyl sulphate (SDS) in aratio of 1:1 and the other with Tween 80. Remarkably, it was seen thatcombination of stabilizers did not affect the crystallinity of drug whencharacterized by DSC; however a reduction of melting point was seendue to generation of new crystalline state [53].

PVP K17 and K12 demonstrated the versatile applications of PVPwhen they were tried for the preparation of probucol nanocrystals.The study established the fact that PVP or SDS alone was incapable toprevent agglomerationwhereas combination of both resulted in a stableformulation. In this work researchers used two different grades of PVP(K12 and K17) in combination with SDS and found that a stable formu-lation was obtained with use of PVP K17 and SDS in comparison to PVPK12 and SDS due to sufficient coverage of drug surface [54]. Similarly,Douroumis et al., proved that a blend of PVP K12 and PVP K17 withhydroxypropylmethyl cellulose (HPMC) provided excellent stability tocarbamazepine nanocrystals. There was a remarkable improvement inthe stability of the formulationwhich contained PVP K17 in the stabiliz-er mixture [55].

3.3. Polyvinyl alcohol (PVA)

Properties of the water soluble PVA are dependent upon the degreeof polymerization and extent of hydrolysis. Partially hydrolysed PVA isgenerally used in pharmaceutical industry [42]. It has been used in for-mulating stable nitrendipine (a class II calcium channel blocker)nanocrystals through precipitation ultra-sonication method with resul-tant improved dissolution characteristics which in turn increased itsoral bioavailability. A total of six combinations with varying concentra-tions of PVA from 0.1 to 1.5% were formulated and the formulationcontaining 0.2% PVAwas found to be sufficiently stable for over a periodof six months [56].

3.4. Amino acid derived co-polymers

Albumin, a single polypeptide chain of 585 amino acids, is generallyused as stabilizing agent for parenteral formulations containing proteinand enzyme. Leucine (C6H13NO2) has gained usage as a lubricant and ananti-adherent in the development of aqueous nanocrystal formulation.Lee et al., tried combination of various co-polymers derived fromamino acids to stabilize nanocrystals consisting of naproxem. Nano-formulations were developed using two polymeric combinationsmade of lysine, leucine, and albumin. Out of these two combinations,lysine (hydrophilic moiety) and leucine (hydrophobic moiety) werefound to be successful in achieving the required particle size and stability[42,57].

3.5. Brij-78

Commonly, used as emulsifying, wetting and a permeation enhanc-ing agent, Brij-78 is a non-ionic surfactant containing polyoxyethylenealkyl ethers and also termed as Cremophor. Nanocrystals obtained byprocessing oridoninwere stabilized using Brij-78 byGao et al. However,its use is often associated with anaphylactic hypersensitivity reactions,

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hyperlipidaemia, abnormal lipoprotein patterns, aggregation of eryth-rocytes and peripheral neuropathy [58].

3.6. Lecithin

These are considered as a mixture of phosphatides with triglycer-ides, fatty acids and carbohydrates. Due to their lipid content, theyform an integral part of many nutritional formulations. When used inpharmaceutical industry, they excel as stabilizer or emulsifiers. Theirphysical forms may vary from being powders or semi liquids based ontheir free fatty acid content and they also pose good absorption enhanc-ing property [42]. Being derived from natural sources (egg and soya),they find wide acceptance as stabilizer for a variety of drugs. Lecithinwas used in combination with poloxomer 188 and HPMC to stabilizeamoitone B, an anticancer agent. Different batches were preparedwith varying concentrations of stabilizers keeping zeta potential andsize as optimization factors. Combination of poloxomer 188 and lecithin(1:1)was found to produce a stable formulation. HPMC failed to providedesired stability since it did not adopt dual stabilization mechanism ofsteric and electrostatic repulsion as executed by lecithin [59]. In astudy elsewhere, twenty different stabilizers were screened preliminar-ily to formulate curcumin nanocrystals, amongst which lecithindisplayed best suspending capability along with its combination withSDC. Maximum steric and electric repulsion offered by the blend of sta-bilizers were responsible for stabilization of nanocrystals [60]. Lecithinhas also been applied for development of RMKP 23 (an antibacterialcompound), prednisolone and carbamazepine bearing nanocrystals[61]. Yang et al., have employed dipalmitoyl phosphatidylcholine (a lec-ithin; endogenous component of human lung surfactant) to formulatenebulized itraconazole nanocrystals with improved bioavailability. Thepresence of dipalmitoyl phosphatidylcholine ultimately improved theoverall in-vivo presence of itraconazole due to its permeation enhance-ment property [62].

3.7. D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS/TPGS 1000)

Vitamin E TPGS an FDA approvedwater soluble compound is a waxyliquid and produced by esterification of vitamin E with PEG 1000. Apartfrom being a very good emulsifier, it also has P-glycoprotein (P-gp)inhibiting property. It is being increasingly employed to overcome bio-availability issues associated with poorly soluble compounds especiallyin case of anticancer drugs [63] where it helps to overcome the MDR.The benefits of TPGS have been used in the formof sole surfactant or sta-bilizer in the formation of paclitaxel nanocrystals againstMDR cells [64].

It has served as an optimal stabilizer in many formulations likebaicalin (flavone) nanocrystals where it is used along with SDS, HPMC,poloxomer 188 and methyl cellulose. Out of all baicalin nanocrystals,the batchmanufactured using TPGS showed the minimummean diame-ter (0.513 μm) and maximum redispersibility following lyophilization.Here, the fully extended polymer chain of TPGS efficiently counter-balanced the stresses induced during freeze drying and ultimatelyprevented particle agglomeration [65].

NVS-102 (a compound synthesised by Novartis Pharma) wasconverted into its nanocrystalline form using TPGS as a stabilizingagent. NVS-102 nanocrystals were produced using wet media millingtechnique and the effect of vitamin E TPGS on size and its oral absorp-tion was investigated. Encouraging results depicted by narrow sizedistribution, increased absorption rate, extended stability and con-trolled Ostwald ripening showcased the feasibility of TPGS stabilizednanocrystals [66].

3.8. Polysorbate 80

A polyoxyethylene sorbitan fatty acid ester derivative has establisheditself as an important pharmaceutical excipient. They are classified

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according to type of fatty acid moiety which influences their functions. Ithas been utilized on the large scale as surface active agent however itspropensity towards causing hypersensitivity [67], birth weight reductionin infants [68] and other side effects when used in high concentration cansometimes be a deterrent. Therefore, researchers often tend to utilizepolysorbate 80 at low levels as a complimentary stabilizer. It has beentried in combinationwith poloxomer 188, PVA, PVP and SDS for develop-ing fenofibrate nanocrystals [69].

3.9. Sodium lauryl sulphate

A sulphuric acidmonododecyl ester sodium salt, is an anionic surfac-tant usedwidely as awetting agent however it exertsmoderate toxic ef-fects including irritation of the eyes, skin and stomach. It has been usedto developed nanocrystals of herpetrione, an antiviral agent extractedfrom herpetospermum caudigerum, via high pressure homogenizationtechnique followed by freeze drying. The powder X-ray diffraction stud-ies revealed that therewas no interaction or alteration in the true natureof the drug by the stabilizer and an overall increase in the oral bioavail-ability was reported [70].

3.10. HPMC

It is a widely used GRAS listed pharmaceutical excipient that hasfound special use in formulation of nanocrystal and is believed tocover the surface of crystal efficiently providing sufficient stability. Incomparison to other stabilizers, its relatively high melting point makesit a robust option for production methods which involve high process-ing temperature. Recently, Ali et al., utilized HPMC as a stabilizingagent inmediamilling process of hydrocortisone nanocrystals intendedfor ophthalmic delivery. HPMC played a key role in stabilizing thenanocrystals by completely covering the surface of dried particle andgave it a low zeta potential. When combined with polysorbate 80 andPVP it rendered stability to the formulation for a period of more than2 months [31]. In another study, Figueroa et al., prepared HPMC basedfenofibrate, naproxem, and griseofulvin (BCS class-II drug) nanocrystals.Inferences showed that HPMC was able to maintain the crystallinity ofthe bioactives [71].

Hecq et al., used HPMC for producing nanocrystals of nimodipineusing high pressure homogenization. The technology was utilizedwith the aim of formulating nanocrystals to improve the dissolutionrate of nifedipine. The use of low viscosity grade HPMC providedadequate stabilizing effect compared to other surface active agentslike SDS, poloxomer and polysorbates [72].

3.11. Sodium cholic acid

Bile acid derived white crystalline powder is employed to stabilizemany nanocrystal based formulations. In combination with poloxomer188, it has been used to stabilize nimodipine nanocrystals. Nimodipineis regarded as a drug of choice for reducing both morbidity and mortal-ity in subarachnoid haemorrhage related vasospasm. The clinicallyavailable injectable form of the drug is administered with alcohol andPEG 4000 which is associated with numerous allergic reactions. The so-dium cholic acid stabilized nanocrystals thus offered a novel approachin which the excipients did not adversely affect the risk–benefit ratioand open an option for intravenous administration of nimodipine [73].It has also been used for stabilization of cyclosporine nanocrystals [74].

4. Ensuring long term stability: drying

Despite, employing myriad of stabilizers and their intricate combi-nations complete preclusion of crystal growth is unavoidable. The inter-play of thermodynamics and molecular kinetics is accelerated in thepresence of a liquid dispersionmedium. Thus, drying of the liquid nano-crystal formulation is often required in conjunction with stabilizers to

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obtain long term stability. Removal of the liquid dispersing thenanocrystals can be attained by two types of drying process: freezeand spray [75,76]. These dried crystals so obtained can be processedinto suitable solid dosage form like tablet or capsule [77,78]. Caremust be taken to ensure that the rapid dissolution characteristics ofthe nanocrystals must not be affected during the abovementioned pro-cessing. In no case, wetting and disintegrating properties of the devel-oped solid dosage should play rate limiting role in the sequence ofevents which dictate the dissolution of nanocrystals [79]. Also, incorpo-ration of nanocrystals in the tablet dosage form is limited to low dosedrugs since higher dose can cause aggregation of nanocrystals withinthe tablet matrix. With reference to freeze drying, the type and amountof cryoprotactant play a crucial role in maintaining the highly sensitivestructural features of nanocrystals. Absence of cryoprotactant leads toformation of non-frozen liquid micro phase resulting in phase separa-tion into ice and cryo-concentrated solution. This causes selective segre-gation of nanocrystals in the small non-frozen liquid pockets increasingtheprobability of particulate aggregation. Considerable amount of stressobserved during freezing and dehydration further destabilizes the col-loidal system. Therefore matrix formers like soluble sugars (sucrose,glucose, mannitol, trehalose, etc.) are added to the formulation beforecarrying out freeze drying which causes immobilization of thenanocrystals thereby forming a protective shield capable of withstand-ing mechanical stress and aggregation [80].

5. Fate of nanocrystals in biological environment

Frommany years, emphasis has been laid onto the benefits garneredfrom nanotechnology however nano-toxicity related issues have alsobeen simultaneously cropped up [81]. Several studies reported possibleentry of nano-particulate formulations into individual cells hinderingthe immune system [82–84]. Therefore, tracing the in-vivo movementof nanocrystals becomes exceedingly important. Fate of nanocrystalsin biological environment is a controversial topic, as a wide spectrumof reports is available in this regard. Some groups of investigators haveclaimed involvement of specialized transports for nanocrystalswhereas,others prioritize solubilisation followed by absorption of hydrophobicdrugs fabricated as nanocrystals [85,86]. Thus, providing a concreteanswer to the query “what exactly happens to nanocrystals in biologicalenvironment?” is a tricky debate.

The primary concern about the fate of nanocrystals is route of ad-ministration as it ultimately governs the sequence of events throughwhich nanocrystals transpire to reach their active site. Nanocrystalsare expected to behave differently when introduced directly into 5 l ofturbulence free blood circulation and bypassing absorption barriers,varying pH, peristaltic movements, and other modalities associablewith oral delivery.

Anecdotally nano-crystallization technology has been employed toimprove intrinsic solubility of bioactives, the level of which (solubilityincrement) often remains undetermined. As, Fu et al., found out thatnimodipine (poorly water soluble drug) nanocrystals were completelysoluble at 2 μg/ml whereas only partial solubility was attained at200 μg/ml in the same form [87]. Expectantly they concluded that mo-lecular dispersion of nemodipine obtained from solubilized nanocrystalsunderwent classical passive diffusion leaving the scope of specialized ab-sorptive pathways for absorption of the remaining intact nanocrystalswhich did not undergo dissolution.

Despite sharing several traits with other colloidal carriers, nano-crystals do not necessarily adopt similar transport systems [88]. Re-searchers have reported that nanocrystals are preferably absorbed fromthe jejunum instead of the ileumwhich signifies that a distinct absorptionmechanism is probably involved in their translocation [30].

Paracellular pathwaymight be one such route for potential uptake ofnanocrystals. However owing to the strict diametric constriction(b10 Å) of the pores present in between juxtaposed cells, exponentiallylarger nanocrystals (~100 nm onwards) find it difficult to pass through.

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Fig. 4A illustrates paracellular pathway of enterocytes which hinderstransport of nanocrystals. However, some researchers claim theopening of these junctions by the application of some specific chemicals(surfactants) such as sodium deoxycholate which might facilitate theentry of nanocrystals, but there is no adequate experimental evidenceon this [89]. In case of cancer the paracellular uptake at site of actionmay take place owing to the well known enhanced permeability andretention (EPR) effect (high fenestra frequency) [90].

Some nanocrystals are taken up directly by cells via multiple endo-cytotic pathways including clathrin-mediated, non-clathrin mediated(caveolae), macro-pinocytosis, as well as phagocytosis. Fig. 4B demon-strates the above specialized mechanisms of nanocrystal transport viaenterocytes. In order to investigate the clathrin-mediated endocytosisof nanocrystals Zhang et al., employed chlorpromazine (known todisrupt clathrin and thereby clathrin-mediated endocytosis) in cellularuptake studies [30]. They found a significant decrease in the uptake ofnanocrystals which supports their hypothesis of clathrin-assisted endo-cytosis. In continuation of their investigation Zhang and his fellowresearchers explored other possible pathways and found that cellularuptake of nanocrystals was lesser at 4 °C in comparison to 37 °C,which might be attributed to the fact that endocytosis of nanocrystals(which requires energy sources; ATP) might have been diminishedat lower temperature. These experimental findings support the uptakeof nanocrystals via active membrane transport process, most likelyclathrin- and caveolae-mediated endocytosis. After endocytosisnanocrystals possibly become available for lymphatic transport insteadof venous transport. The reasons might be the low pore size (roughly 3nm) of the vascular epithelium. Reports on the uptake of nanocrystals

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Fig. 4. (A) Graphical representation of intracellular tight junction and failure ofnanocrystals to pass through paracellular pathway, (1) enterocytes, (2) intracellulartight junction (b10 Å), and (3) failure of nanocrystals to pass through the paracellularpathway. (B) Diagrammatic representation of clathrin-mediated, and non-clathrin (cave-olae) mediated endocytosis of nanocrystals after oral administration, (1) nanocrystals onthe enterocyte surface, (2) magnified view of nanocrystals over the cell membrane,(3) clathrin-mediated phagosome and endocytosis of nanocrystals, (4) release ofnanocrystals to the other side of cell via clathrin-mediated transport, (5) non-clathrin (caveolae) mediated endocytosis of nanocrystals, and (6) release of nanocrystalsto the other side of cell via non-clathrin (caveolae) mediated transport.

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via M-cells are also found in literature. These specialized cells arebelieved to transport nanocrystals through an active transepithelialvesicular transport system from the lumen directly to lymphoid cellsand tissues; though the overall efficiency of this process remains ques-tionable as M cell populates less than 1% of the intestinal epithelia [91].

Following intravenous administration, nanocrystals may remainintact or enter into a molecular dispersion due to high intrinsic solubil-ity, dissolution rate, and rapid dilution accessing the site of action fortherapeutic effect [92]. Alternatively intact nanocrystals keep movingin the systemic circulation as colloidal particles. During their flight,nanocrystals are recognized as foreign bodies and engulfed by thedefence (phagocytic) cells such as macrophages. In phagocytic cellsnanocrystals dissolve slowly in phagolysosomes. Consequently, the hy-drophobic drugmight pass through the phagolysosomalmembrane andenter into the cytoplasm, and then diffuse out of the cell down its con-centration gradient [93]. Fig. 5 depicts the fate of nanocrystal after intra-venous administration. Nanocrystals of size less than 100 nm behavelikemolecular solutionwhereas those greater than 500 nmare accumu-lated in the liver. This characteristic of nanocrystals can be successfullyused in targeting different diseases/disorders [94].

To summarize nanocrystals and their uptake are not fully under-stood although several studies have reported various mechanisms aswell as pathways.More detailed in vivo experiments at pre-clinicalmea-sure are required for the complete elucidation of mechanisms involvedin the in vivo fate of nanocrystals.

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6. Applications

6.1. Oral drug delivery

Oral route has been the most preferred route and is considered asthe safest and suitable route for drug delivery [95]. For orally adminis-tered drugs, dissolution is considered as a rate determining step for ab-sorption [96]. Nanocrystals provide a greater surface area for dissolutionand thus raising the saturation solubility which ultimately increases thedissolution rate thereby enhancing drug absorption. Rapamune® wasthe first US FDA approved oral nanocrystals launched in the year 2000by Wyeth Pharmaceuticals (Madison, NJ). It consisted of sirolimus

Fig. 5. Proposed in vivo fate of nanocrystals after intravenous administration (1) injectionof nanocrystals to blood vessels, (2) nanocrystals in the blood stream inmolecular solutionand intact nanocrystal form, (3) phagocytic cells, (4) formation of molecular solutions ofnanocrystals in blood, (5) phagocytosis of intact nanocrystals and further solubilizationin cytosol of phagocytes, and (6) drug in molecular solution form comes out due toconcentration gradients of phagocytes and outer environment.

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t2:1 Table 2t2:2 Drug delivery routes explored by nanocrystals.

Drug Manufacturing technique Mean particle size Use/benefits Referencet2:3

Oral deliveryt2:4

Danazol Media milling 169 nm Hypoestrogenic and hyperandrogenic activity/a 16 fold increase in bioavailability in comparison to danazol suspension [18]t2:5

Ketoprofen Media milling 265 nm Rheumatoid arthritis/1.2 fold increase in Cmax and 2 fold reduction in Tmax in comparison with microcrystalline ketoprofen [116]t2:6

Fenofibrate HPH 356 nm Lipid lowering agent/12.5 fold increase in Cmax and 17 fold increase in bioavailability [117]t2:7

Cyclosporine HPH 962 nm Autoimmune disease [74]t2:8

Itraconazole Precipitation 267 nm Antifungal/1.5 and 1.8 fold higher bioavailability from commercial product in the fed and fasted states [118]t2:9

Icaritin Antisolvent-crystallization method underultrasonication

220 nm Prevent osteoporosis/faster dissolution, improved absorption and grater in-vivo bioactivity than raw suspension [119]t2:10

Paraterphenyl derivative Precipitation followed by HPH 200 nm Promising anticancer agent/increased saturation solubility, accelerated dissolution and 5 fold higher AUC withsignificantly longer MRT in comparison to its solution

[120]t2:11

Cilostazol Anti-solvent and high-pressurehomogenization method

326 nm Vasodilator/enhanced AUC and Cmax was observed in comparison to marketed formulation [121]t2:12

t2:13Intravenous deliveryt2:14

Oridonin HPH 103.3 nm Anticancer/improved bioavailability in comparison to its solution [122]t2:15

Ascularine HPH 133 nm Anticancer/2.3, 6.2, 2.7 and 2.7 fold increase in t1/2, Vd, CL, and MRT in comparison to ascularine solution [47]t2:16

Curcumin HPH 210.2 nm Anticancer/3.1 fold increase in Cmax, 11.2 fold increase in MRT and 4.8 fold increase in AUC [60]t2:17

Flurbiprofen HPH – Rheumatoid arthritis/improved bioavailability [123]t2:18

Atovaquone HPH 279 nm Improved activity against toxoplasma encephalitis due to enhanced bioavailability [124]t2:19

t2:20Pulmonary deliveryt2:21

Itraconazole Precipitation Less than 1 μm Antifungal [125]t2:22

Budesonide – Less than 1 μm Anti-asthmatic [126]t2:23

Buparvaquone – – Antiprotozoal [127]t2:24

Sildenafil Precipitation – Erectile dysfunction and pulmonary hypertension [128]t2:25

Carvedilol Solvent precipitation-ultrasonicationmethod

190 nm Antihypertensive [45]t2:26

t2:27Ocular deliveryt2:28

Hydrocortisone Precipitation 300 nm Steroid/1.8 fold increase in AUC [31]t2:29

Forskolin Wet milling 164 nm Antiglaucoma agent/improved intraocular pressure lowering efficacy than its solution form [109]t2:30

Cyclosporin A In-situ precipitation 505 nm Immunosuppressant/improved bioavailability [129]t2:31

Mycophenolate mofetil HPH 440 nm Immunosuppressant/modified corneal drug disposition [130]t2:32

t2:33Dermal deliveryt2:34

L-Ascorbic acid Emulsification + homogenization 148 nm Antioxidant/long-term stable topical formulation without decomposition [114]t2:35

Lutein HPH 429 nm Antioxidant [115]t2:36

Hesperetin HPH 300 nm Antioxidant and antiallergic [52]t2:37

Tretinoin Precipitation 324 nm Anti-acne agent [131]t2:38

Ibuprofen Wet milling 284 nm Analgesic [132]t2:39

8V.K.Paw

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drugdelivery,J.Control.

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nanocrystals incorporated in an excipientmixture suited for direct com-pression into palatable tablets. The oral bioavailability of the nanocrystaltablets was 21% higher compared to sirolimus solution [97].

The various advantages of nano size have been used to favourablymodulate pharmacokinetic profile of aprepitant (EMEND®) which fol-lows absorptionwindow phenomenon in the gastrointestinal tract [98].

Nanocrystal technology has been known to even-out discrepanciesbetween fasted and non-fasted bioavailability of fenofibrate which ispractically insoluble in water. Normally it requires bile and relatedsurfactants secreted postprandially for absorption. Nanomerisation offenofibrate enhances its solubility making it bioequivalent in fed andfasted conditions [99].

Muller et al., have refined oral delivery of thermo stable drugs utilizingmelted PEG (melting point at 60 °C) which allows fixing of nanocrystalsin a solid PEG matrix. Nanocrystals dispersed in melted PEG were milledto powder and directly compressed into the tablet or filled in capsulesshell [29]. Thus, this novel drug delivery system offers a way to incorpo-rate poorly soluble drugs directly into tablet, capsule or hot melts solidmatrix to improve oral bioavailability.

6.2. Intravenous drug delivery

Administering a drug via intravenous route provides numerousbenefits such as immediate action, reduced dosing and 100% bioavail-ability. These benefits can be considered as ideal parameters for everydrug but the use of intravenous route is limited because harmful solventand excipients, which are used during formulation development, arealso co-administered with the drug and they can cause serious side

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Fig. 6. EPR effect; (A) Normal vessel: the narrow gap junctions present in between endothelial cthe ordered structure of cells in the presence of functional lymphatic drainage. Lymph flow regdothelium in and around tumour is disjointed, irregular and leaky allowing effective penetratthese particles leading to their enhanced accumulation at tumour site.

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effects other than the drug itself [51,100]. Under such circumstances,nanocrystals could be considered as the ideal candidates for intravenousdelivery because their developmental processes do not employ excessuse of such harmful excipients. During development of a novel drugdelivery system to be delivered through parenteral route, it must bekept in mind that the carrier system should not be phagocytosed by re-ticuloendothelial system as well as by Kupffer cell present in the liver.Thus, size range of ≤100 nm is preferred for parenteral nanocrystals[7]. Nanocrystals of drugs such as ascularine [47], melarsoprol [16],oridonin [58], itraconazole [51], and curcumin [60] have been success-fully developed thereby providing benefits like increase in Cmax, andAUC. These benefits are an open invitation to pharmaceutical scientistsfor exploiting nanocrystals comprising water insoluble notorious drugsfor intravenous delivery.

6.3. Pulmonary drug delivery

Lungs are highly perfused organs with a fully expanded surface arearoughly equivalent to three football fields.With no hepatic portal drain-age, molecular dispersion of drug transport is rapid with high efficiencyinto the systemic circulation. Recently, it has been demonstrated thatpulmonary nanocrystals have the ability to rival pharmacokineticsoffered by intravenous administration of baicalin [101]. Pulmonaryroute thus comes across as a viable option for delivery of therapeutics.Due to constant exposure to external environment, it is highly suscepti-ble to disease causing agents; allergens and pathogens easily invadethrough the respiratory tract [102]. Conventional modalities ofdeep lung drug deposition have been modified by tailoring size of

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ells allow only small molecules to penetrate, screening out colloidal sized particles. Noticeularly filters out accumulated material. (B) Tumour microenvironment: The vascular en-ion of nanocrystals. Absent or dysfunctional lymphatic vessels further delay clearance of

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t3:1 Table 3t3:2 Various disease states targeted by nanocrystals.

Disease Drug Mfg. technique Route Benefits Referencet3:3

Cancer Melarsoprol HPH i.v. Improved in-vitro antileukemic activity in comparison to its hydroxypropyl-β-cyclodextrininclusion complex

[16]t3:4

Hydroxy camptothecin Precipitation-combined HPH i.v. Nanocrystals showed higher in-vitro cytotoxicity against cancer cells than its injection form [150]t3:5

Paclitaxel Precipitation followed by sonication i.v. Significant anti-tumour efficacy of nanocrystals over taxol. [64]t3:6

Oridonin HPH i.v. Improved in-vitro cytotoxicity and in-vivo anti-tumour activity were obtained in comparisonto oridonin solution.

[142]t3:7

Paclitaxel & camptothecin 3-Phase nanoparticleengineering technology

Oral & i.v. Enhanced antitumour activity due to targeting folate receptors [147]t3:8

Oridonin HPH – Improved cytotoxicity and apoptotic activity against PC-3 cell line in comparison to its solution [143]t3:9

Docetaxel HPH i.v. Docetaxel nanocrystals proved a better opportunity to inhibit tumour growth and reducetoxicity in comparison to marketed formulation.

[145]t3:10

Camptothecin Precipitation followedby sonication

i.v. Prepared nanocrystals had 5 times more concentration in tumour compared to drug solutionwith a proven stability for six months.

[30]t3:11

Oridonin HPH i.v. Effective inhibition of SMMC-7721 cells was found using oridonin nanocrystals and furtherconfirmed by higher in-vivo anticancer activity in comparison free oridonin

[144]t3:12

Silybin HPH – Low bioavailability and poor aqueous solubility limited the use of silybin as an anticanceragent. Use of nanocrystal technology lead to development of aformulation which showed higher anticancer activity against prostatic cancer than the silybinsolution.

[151]t3:13

Bicalutamide Anti-solvent precipitation Oral Nano sizing showed a significant improvement in pharmacokinetic profile of the drug after oraladministration indicated by 3.5 times raised Cmax and AUC in comparison to free drug.

[152]t3:14

2-Methoxyestradiol (2-ME) Nano precipitation high frequencyultra-sonication

i.v. Nanocrystals showed significantly better tumour inhibition activity than its solution form. [153]t3:15

Amoitone B HPH Oral The formulated nanocrystals led to an increased dissolution velocity and magnified AUCcompared to amoitone b solution.

[59]t3:16

Puerarin HPH i.v. Puerarin nanocrystals showed a better in-vivo tolerability and higher anticancer efficacy thanits free solution.

[154]t3:17

Riccardin D Combination technologies – Nanocrystals exhibited improved solubility and dissolution profile. Particle size affects thepharmacokinetics and biodistribution of nanocrystals. Big particles were uptaken byreticuloendothelial system at high level than smaller particle.

[155,156]t3:18

PIK75 HPH – 11 fold improvement in saturation solubility [148]t3:19

SKLB610 Wet media milling Oral 2.6 fold higher bioavailability was observed in comparison to simple suspension of drug [157]t3:20

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HIV/AIDS/anti-viral Nevirapine HPH i.v. The nano sizing resulted in better accumulation of drug in different organs of rat compared toplain drug evidenced by higher MRT values in brain, liver and spleen.

[137]t3:21

Rilpivirine Wet milling i.m./s.c. Results demonstrated that size of nanocrystals significantly influence the pharmacokineticprofile of drug. Nanocrystals having size around 200 nm showed higher plasma drug concentrationin comparison to nanocrystals having size 400 and 800 nm.

[158]t3:22

Efavirenz Media milling Oral Nanocrystals provide improved bioavailability due to enhanced solubility, dissolution velocity,permeability and absorption in comparison to marketed formulation.

[159]t3:23

Herpetrione HPH Oral Significant higher AUC and Cmax with improved efficacy in comparison to coarse drug suspension [70]t3:24Haemorrhoids andvenous leg ulcers

Diosmin Precipitation – 89% drug permeated from intestine in ex-vivo study [160]t3:25

Malaria Atovaquone Microprecipitation with HPH Oral 4.6 and 3.2 fold higher AUC in comparison to drug suspension and marketed formulation [161]t3:26Fungal infections Nystatin Wet media milling Intra oral Lowered oral burden of Candida albicans with no systemic absorption [162]t3:27Organ targeting Amphotericin-B (brain) HPH Nanocrystals coated with polysorbate 80 and sodium cholate showed enhanced brain uptake

than amphotericin b solution.[163]t3:28

Atovaquone (gastrointestinaltract and brain)

HPH Oral An approach was made for the treatment against toxoplasmic encephalitis caused due toToxoplasma gondii.The treatment by atovaquone shows poor oralbioavailability. Thus, development of atovaquone nanocrystals using SDS leads to improved oralbioavailability and brain uptake.

[136]t3:29

Diabetes Glibencamide Combination technology Oral Nanocrystals of poorly soluble antidiabetic glibencamide were transferred to fast dissolvingtablets which retained dissolution properties of the drug nanocrystals. Study is of potentialclinical relevance.

[77]t3:30

Hypertension Carvedilol Nano precipitation aided withultra-sonication

Intra-nasal An alternative route of administrating carvedilol so as to bypass heavy first pass metabolismwas explored.An in-situ gelling spray loaded with nanocrystals wasadministered intra nasally to significantly improve the absolute bioavailability in comparisonto oral route.Nanocrystals sub served to increase nasal permeability of drug.

[45]t3:31

Telmisartan Antisolvent precipitation technique Oral 10 fold increase in bioavailability was observed [164]t3:32Candesartan cilexetil Media milling Oral Results suggested that enhanced dissolution velocity and saturation solubility of nanocrystals

extends the bioavailability of drug[165]t3:33

Olmesartan medoxomil Media milling Oral Nanocrystals seem to overcome the poor oral bioavailability of drug. [166]t3:341,3-dicyclohexylurea Wet-milled Oral/subcutaneous Subcutaneous route was found to suitable for administration of nanocrystals rather than oral. [167]t3:35

Antipsychotic—bipolarmania

Ziprasidone Wet milling Oral Nanocrystals improved the fasted state bioavailability in beagle dogs when compare tocommercially available capsules.

[168]t3:36

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nanocrystals. A nebulizer is generally required to administer powderednanocrystals. Nebulizer can incorporate nanocrystals into small inhalabledroplets (1–5 μm) [103]. A study showed that aerosolised nanocrystalsenhanced drug bioavailability when compared to inhalable dispersionscontaining microparticles [104]. However, nebulisation is a complexprocess which depends upon variety of factors like droplet size andbreathing pattern. The above technology has been used to deliverbudesonide through pulmonary route [19].

6.4. Ocular drug delivery

Ophthalmic drug delivery is a challenging task owing to criticalpharmacokinetic environment and physiological barriers of the eyethat hinder the delivery of drugs [105].Most of the drugs for ocular ther-apy are delivered through a topical formulation in the form of solutionor suspension [106]. Conventional formulations are subjected to rapidclearance from application site due to rapid eye movements (blinking)and lacrimation, which results in low ocular availability. Short retentiontimeofmedication induces a need of repeated dosing relatablewith lossin patient compliance and dose dependent side effects. To alleviatethese rapid filings, several approaches like ocular inserts and opthalmicgels have been tried, which themselves are associated with fair share ofinadequacies, viz. poor therapeutic outcome, blurred vision and localirritation. Ophthalmic drug deliverywas believed to be benefited largelyby a colloidal drug delivery system. Piloplex, the first novel colloidaldrug delivery system developed, contains pilocarpine which is ionicallybounded to poly(methyl) methacrylate-co acrylic acid nanoparticles[107]. Subsequently, nanocrystal technology played an advanced rolein ophthalmic drug delivery tackling dispersibility issues of poorlysoluble drugs such as budesonide, dexamethasone, hydrocortisoneprednisolone [17] and fluorometholone [108]. Ali et al., used combina-tion technology based upon microfluidic nanoprecipitation and wetmilling to create nanocrystals of hydrocortisone and ocular bioavailabil-ity was evaluated in albino rabbits. Results demonstrated an extendedduration of action and significantly improved AUC of developednanocrystals in comparison to free drug [31]. Amarkedly advanced oph-thalmic delivery system for forskolin (intra ocular pressure loweringagent) was developed by incorporating its nanocrystals into an in-situgelling system comprised of poloxamer and polycarbophil. Pharmaco-dynamic studies revealed that nanocrystals/hydrogel system efficientlylowered the intraocular pressure up to 12 h in comparison to conven-tional suspension [109].

6.5. Dermal drug delivery

Skin is a therapeutic barrier, limiting delivery of many drugs [110].Success in dermal delivery depends upon the permeation of drugsacross stratum corneum [111,112]. Due to their small size, nanocrystalsare expected to pack closely to form an occlusive layer which hydratesthe skin increasing penetration and permeation of drugs. Dispersednanocrystals are retained topically for sufficient time period, slowlyreleasing the active constituent [113]. They have already been triedwith L-ascorbic acid to form a long term stable topical formulation andcontaining nanocrystals in oil base [114]. Suspended nanocrystals oflipophilic compounds like lutein, an antioxidant, showed an increasedpermeation through a synthetic membrane [115]. Table 2 enlists someof the drugs which have been successfully administered throughvarious routes as nanocrystals.

7. Targeted nanocrystals

Nanotechnology has dramatically re-shaped drug delivery in recentyears. It hasmotivated researchers and industrialists to altermethods offormulating newaswell as existing drugs extending their lifespan in theprocess. Unscrupulous drug administration for treating a localizeddisease is no longer acceptable. The extensive adverse effects caused by

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chemotherapeutics intended for benign tumours are one such examplewhere the entire body bears the brunt of non-selective drug distribution.It therefore becomes exceedingly important to designmechanismswhichensure targeted delivery. Targeting of drug molecules against diseasesrequires careful consideration of their physicochemical and biopharma-ceutical properties and it can improve the current therapeutic profile ofvarious active pharmaceutical ingredients.

Targeting approach has also been implemented with nanocrystaltechnology for drugs which frequently face challenges like bioavailability,solubility, stability and poor IVIV correlation [133,134]. Bupravaquonenanocrystals suspended in a mucoadhesive system were used fortargeting Cryptosporidium parvum, a gastrointestinal parasite. Thenanocrystals showed a better targeting and were considerably morestable thanpure bupravaquone [135]. Surfacemodification of atovaquonenanocrystals with surfactants like SDS was reported to enhance its brainuptake and efficacy to decrease parasite load (Toxoplasma gondii) in com-parison to commercial micronized atovaquone suspension (Wellvone®)oral administration of 100 mg of drug/kg [136]. In a recent study, poorlysoluble anti-retroviral nevirapine was converted into nanocrystals usingcold HPH followed by surface modification with serum albumin, dextranand PEG. The rank order found for macrophage (residence site of HIV)uptake was as follows: serum albumin coated N dextran coated N PEGcoated N uncoated nanocrystals N free drug. Formulation coated withserum albumin showed at least four fold higher macrophage uptakethan free drug. Biodistribution studies in rats for nanocrystals revealed in-creased drug accumulation in the brain, liver and spleen in comparison tofree drugwhen administered intravenously [137]. Surfacemodification offabricated nanocrystals can bring the site specific targeting. Surface label-ling of nanocrystals with fluorescentmarkers has beenwidely utilized fordiagnostic consequences for exampleWilliams et al., modified the surfaceof silicon-substituted hydroxyapatite nanocrystals through a silanefollowed by grafting fluorescein-5-maleimide to accommodate real-time biological cell trafficking. Hydroxyapatite nanocrystals residence inpre-osteoblast cells was confirmed by observing fluorescence up to 24 hwithout quenching. It was also forecasted that developed nanocrystalswould open the door for successful intracellular delivery of growth factors[138].

Cancer presents yet another opportunity for exploiting targeteddrug delivery by nanocrystals to tilt the risk–benefit ratio towards im-proved therapeutic outcome [139]. Themicro environment surroundinga tumour is unique and not evidenced in normal vasculature which canbe characterized by narrow junctions between endothelial cells, or-dered cellular arrangement and adequate lymphatic drainage. However,vessels in and around tumour are characterized by irregular endothelialcell lining, lack of pericytes, and an indecorously developed smoothmusculature with randomly dispersed collagen. This improper arrange-ment of endothelial cells leaves gaps of micron range in the tumourvasculature which can be easily permeated by nanocrystals. Contribu-tion of hypoxia and acidosis was also seen due to disturbedmicrovascu-lature [140]. Additionally, lymphatic vessels are either absent orineffective causing inefficient drainage from the tumour tissue leadingto effective retention or accumulation of the drug carriers (EPR effect).The EPR effect/passive targeting also prevents undue toxicity by provid-ing selective localization of drugs [141] (Fig. 6). Nanocrystals with theirunique size achieve a new biodistribution profile which is not possiblewith simple micronization of drugmolecules. Zhang et al., whilst inves-tigating the in-vivo anti-tumour effect of camptothecin nanocrystals inMCF-7 xenografted Balb/C mice observed significant tumour suppres-sion due to their five-fold higher tumoural accumulation in comparisonto camptothecin solution. They attributed enhanced efficiency ofnanocrystals to EPR effect [30]. Different studies demonstrated thatoridonin nanocrystals were found to show enhanced apoptotic activityin prostatic PC-3 cell line and SMMC-7721 cells along with betterin-vivo tumour inhibition profile in comparison to oridonin solution[142–144]. In another study, soya lecithin stabilized docetaxelnanocrystals were prepared using HPH. The in-vivo pharmacokinetics,

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tissue distribution as well as anti-tumour studies in B16 melanomabearing Kunming mice suggested that intravenous administration ofdocetaxel nanocrystals could effectively ameliorate tumour growthand reduced toxicity by increasing accumulation of docetaxel withintumour sites in comparison to marketed product [145].

Resistance to therapy is an adaptive strategy undertaken by the can-cer cells to nullify the advantages acquired through passive targeting.Structural incongruity is never consistent leading to altered permeabil-ity and blood supply. To overcome such hurdles and, sometimes to aug-ment passive targeting, ligands selective for receptors overexpressed oncancer cells are appended to nanocrystals. This opens up the avenue foractive receptor based targeting by tailoring nanocrystals [146]. Liu et al.,described the concept of proof by activating paclitaxel nanocrystalsthrough application of folic acid conjugated stabilizer. In comparisonto non-ligated paclitaxel nanocrystals, ligated nanocrystals showedenhanced in-vitro cytotoxic activity due to preferential uptake viaoverexpressed folic acid receptor on KB cells [147]. In another study,folate receptors were targeted using PTK75 nanocrystals stabilizedwith poloxamer conjugated to folic acid and in-vivo studies indicated10 fold increased accumulation of drug in tumour [148]. An attemptwas made to shed further light on the detailed mechanism elucidatingactive cancer targeting by Huang and associates. They carried outquantitative tumour uptake studies on PEG stabilized columnar goldnanocrystals covalently attached to targeting peptides responsive to re-ceptors selectively populating the cancer cells. Gold nanocrystals wereconjugated to three different ligands, namely: a single-chain variablefragment which attaches to epidermal growth factor receptor; aminoterminal fragment peptidewhich acts on theurokinase plasminogen ac-tivator receptor; and cyclic RGD peptide capable of binding on integrinreceptor. Although the results of the study revealed a marginal incre-ment in drug accumulation in comparison to non-targeted nanocrystals,they could greatly influence the cellular uptake of gold; illustrating howactive homing device can synergise with passive size based targeting incancer therapy [149]. The space of actively targeted nanocrystals is stillvoid and needs to be carefully followed to produce commerciallysuccessful products. Various diseases approached by nanocrystals aresummarised in Table 3.

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8. Conclusion

Taking into account potential advantages and reduced side effects,nanocrystals are considered as suitable candidates for in-vivo delivery ofpoorly soluble drugs. It is a unique approach to solve bioavailability relat-ed issues. Industrially feasible manufacturing techniques have served tobring nanocrystals from researcher's bench to patient's bed at an acceler-ated rate. Nanocrystals are versatile pharmaceuticals which can be deliv-ered through almost all routes of administration such as oral, parenteral,dermal, and ocular. They are adept to convenient sterilization techniques,a key driver for development of parenteral formulations. Incorporation ofappropriate stabilizers followed by drying (freeze/spray) can ensure longterm stability of nanocrystals. Dried nanocrystals are suitable for pharma-ceutical processing like granulation which might usher a new era ofsecond generation nanocrystals. Nanocrystals decorated with functional-ized ligands have generated a new ray of hope by being able to target var-ious organs with higher affinity. Furthermore, nanocrystals might be anopportunity to produce generic versions of presently available costlydrugs. In conclusion, engineered nanocrystal technology has huge poten-tial to deliver pre-existing or newly developed notorious (poorly aqueoussoluble) drugs in a more acceptable and effective dosage form with highcommercial applicability.

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