A Review: Pharmaceutical and Pharmacokinetic Aspect of Nanocrystalline Suspensions

Nanocrystals have emerged as a potential formulation strategy to eliminate the bioavailability-related problems by enhancing the initial dissolution rate and moderately super-saturating the thermodynamic solubility. This review contains an in-depth
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  REVIEW A Review: Pharmaceutical and Pharmacokinetic Aspectof Nanocrystalline Suspensions DHAVAL A. SHAH, 1 SHARAD B. MURDANDE, 2 RUTESH H. DAVE 1 1 Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York 11201 2 Drug Product Design, Pfizer Worldwide R&D, Groton, Connecticut 06340  Received 7 August 2015; revised 23 September 2015; accepted 25 September 2015 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24694 ABSTRACT:  Nanocrystals have emerged as a potential formulation strategy to eliminate the bioavailability-related problems by enhancingthe initial dissolution rate and moderately super-saturating the thermodynamic solubility. This review contains an in-depth knowledge of,the processing method for formulation, an accurate quantitative assessment of the solubility and dissolution rates and their correlation toobserve pharmacokinetic data. Poor aqueous solubility is considered the major hurdle in the development of pharmaceutical compounds.Because of a lack of understanding with regard to the change in the thermodynamic and kinetic properties (i.e., solubility and dissolutionrate) upon nanosizing, we critically reviewed the literatures for solubility determination to understand the significance and accuracy of theimplemented analytical method. In the latter part, we reviewed reports that have quantitatively studied the effect of the particle size andthe surface area change on the initial dissolution rate enhancement using alternative approaches besides the sink condition dissolution.The lack of an apparent relationship between the dissolution rate enhancement and the observed bioavailability are discussed by reviewingthe reported  in vivo   data on animal models along with the particle size and food effect. The review will provide comprehensive informationto the pharmaceutical scientist in the area of nanoparticulate drug delivery.  C   2015 Wiley Periodicals, Inc. and the American PharmacistsAssociation J Pharm Sci Keywords:  nanocrystals; nanosuspensions; nanoparticles; solubility; dissolution; pharmacokinetics; food interactions; bioavailability;particle size reduction INTRODUCTION Recent advances in synthetic, analytical, and purificationchemistry, along with the development of specialized toolssuch as high-throughput screening, combinatorial chemistry,and proteomics, have led to a sharp influx of discovery com-pounds entering into development. Many of these compoundsare highly lipophilic, as the  in vitro  screening techniques placeconsiderableemphasisontheinteractionofcompoundswithde-fined molecular targets. In recent years, it has been estimatedthat up to 70% of the new drugs discovered by the pharmaceu-tical industry are poorly soluble or lipophilic compounds. Pooraqueous solubility is one of the major hurdles in the develop-ment of new compounds into oral dosage forms, as absorptionis limited by dissolution for these compounds. 1 The well-known Biopharmaceutics Classification System(BCS) is frequently used to categorize pharmaceutical com-pounds. According to the BCS system, poorly soluble com-pounds belong to Class II (low solubility, high permeability)or Class IV (low solubility, low permeability). In another words,we can also say that Class II and IV compounds provide moreopportunities for the development of newer technologies toovercome the solubility- or dissolution-related issues based onchemical and physical properties of the compounds. This per-ception is widely used and well established within the pharma-ceutical industry. However, using the BCS system for guidancein formulation selection may sometimes oversimplify the com- Correspondence to : Rutesh H. Dave (Telephone:  + 718-488-1660; Fax:  + 718-780-4586; E-mail: Rutesh.Dave@liu.edu)Journal of Pharmaceutical Sciences C  2015 Wiley Periodicals, Inc. and the American Pharmacists Association plex nature of drug dissolution, solubility, and permeability.Poorly water-soluble compounds can possess such a low aque-ous solubility that the dissolution rate, even from micronizedparticle, is very slow. In this case, it is not possible to reach suf-ficiently high drug concentrations in the gastrointestinal tractfor an effective flux across the epithelial membrane. Other fac-tors, such as efflux transport or pre-systemic metabolism, canalso negatively influence oral bioavailability.Therefore, it is recommended to classify compounds intoslightly different categories, as they can show dissolutionrate-limited, solubility-limited, or permeability-limited oralbioavailability. Butler and Dressman 2 designed the “Developa-bility Classification System (DCS),” as another way to catego-rizecompoundsinamorebio-relevantmanner.Thissystemdis-tinguishes between dissolution rate-limited compounds (DCSClass IIa) and solubility-limited compounds (DCS Class IIb).In order to select the right formulation approach and to ad-dress the compound-specific issues with a suitable formulationtype,itisimperativetofirstunderstandthebioavailabilitylim-iting factors. Selection of the right formulation approach is oneof the key activities for formulators in the pharmaceutical in-dustry. Key factors include the physicochemical properties of active pharmaceutical ingredient (API), such as aqueous solu-bility, the melting point temperature, and chemical stability. Inaddition, the formulator needs information about the potencyof the compound and the desired route of administration to de-termine the type of final dosage form as well as the requireddrug load. All these factors can be considered in decision trees,which are often used in the industry to guide the formulator.However, there are some biopharmaceutical-relevant as-pects that need more attention in order to avoid false nega-tive results. In addition, it is also important to note that there Shah, Murdande, and Dave, JOURNAL OF PHARMACEUTICAL SCIENCES  1  2  REVIEW is no uniform approach that solves all the formulation-relatedproblems. Each technology has its own advantages and disad- vantages. Depending on the formulator’s understanding of theinterplay between the physicochemical properties of the drug,the special aspects of the various formulation options and therequired invivo performance,thehigherthechancethattheop-timal formulation approach will be chosen. This minimizes theriskoflatefailuresinthehumanclinicaltrials,forexample,dueto insufficient or highly variable drug exposures. Compoundsshowingdissolutionratelimitedbioavailabilitymaybereferredto as DCS Class IIa compounds, but they represent only onepart of the BCS Class II compounds. The extent of the oralbioavailability of such compounds directly correlates with theirdissolution rate  in vitro . The fraction of the dose that dissolvesin the lumen is readily absorbed through the intestinal mem-brane.Consequently,thebioavailabilityofsuchcompoundscanbe improved by any technique that increases the primarily thedissolution rate. Various formulation approaches are known tolead to increased dissolution rate and bioavailability, includ-ing salt formation, the use of cocrystals, particle size reduction,complexingwithcyclodextrins, 3 microemulsions, 4 andsoliddis-persiontechnologies. 5,6 Theformulatorhastoselecttheoptimalformulation approach based on the properties of a specific drug molecule. However, all these technologies have certain limita-tions and cannot be used as universal formulation techniquesfor all the poorly soluble compounds, especially those whichare insoluble in both aqueous as well as non-aqueous solvents. 7 To prevent the removal of poorly soluble compounds from thepharmaceutical pipeline, a broad-based technology is requiredfor drug molecules that are insoluble or poorly soluble in bothaqueous and non-aqueous solvents. This will have the tremen-dous impact in discovery sciences and will improve the perfor-mance of existing molecules suffering from formulation-relatedissues. 8 In the last two decades, after the introduction of Nanocrystal R   technology, particle-size reduction approaches havegrown to a commercial level. Several formulation ap-proaches have been reported to formulate the nanoparticles,such as nanocrystalline suspensions, Poly Lactic-co-Glycolicacid(PLGA)based nanoparticles, nanosphears, and solid-lipidnanoparticles. By the virtue of their large surface area (SA) d c d t  =  AD ( C s − C ) h ln  S S 0 =  2  MY  D rRT   h H  = k  √   L / √  V   Noyes–Whitney Equation Ostwald–Freundlich Prandtl Equationd c  /d t = Dissolution velocity  S = Solubility at Temp T  h H  = Hydrodynamic boundary layer thickness  A = Surface area  S 0  = Solubility of infinite big particle  k = Constant  D = Diffusion coefficient  M  = Molecular weight  L = length of surface in flow direction C s  = Saturation solubility  D = Density  V  = relative velocity of flowing liquid C = Drug concentration in  U  = Interfacial tensionSolution at time  t R = Gas constant h = Thickness of diffusion layer  r = Radius T  = Temperature to volume ratio, nanocrystals provide an alternative methodto formulate poorly soluble compounds. Nanosizing refers tothe reduction of the APIs’ particle size down to the sub-micronrange.Nanosuspensionsaresub-microncolloidaldispersionsof discrete particles that have been stabilized using a surfactantand a polymer or a mixture of both. 9 Stabilized sub-micronparticles in nanosuspensions can be further processed intostandard dosage forms, such as tablets or capsules, which arebest suited for oral administration.It has been studied and observed that the reduction in par-ticle size in the micron or nano range have a positive impact onthe invitro dissolutionrate,whichcanbeusedtopredict invivo enhancement in bioavailability for poorly soluble compounds. 10 Compound-specific properties, such as high melting point, highlog   P  valueandpooraqueoussolubility,arerequiredtoconsiderbefore the selection of this approach. Therefore, BCS Class IIand IV compounds would theoretically be good candidates forthe nanosizing approach, along with some exceptions, such asfenofibrate (FBT) (low melting point). 11 Drug nanocrystals ex-hibit many advantages, including high efficiency of drug load-ing,easyscale-upformanufacture,relativelylowcostforprepa-ration, and applicability to various administration routes, suchas oral, parenteral, ocular, and pulmonary delivery (Table 1). All these advantages have led to successful promotion of drug nanocrystals from experimental research to patients’ usage.The availability of several products on the market shows thetherapeutic and commercial effectiveness of the approach. 12 The pioneering work of many academics and industrial re-searchers has laid the foundation for broad utilization and ac-ceptance of this approach within the field of pharmaceuticalsciences.By definition, nanosizing is particle-size reduction to 1 and1000 nm. Because of their small size, these particles can varydistinctly in their properties from micronized drug particles.Similarly to other colloidal systems, drug nanocrystals tend toreduce their energy state by forming larger agglomerates orcrystal growth, which is why they are often stabilized with sur-factants, stabilizers, or with a mixture of both. Reduction of theparticle size to the nanometer range results in a substantialincrease in SA (  A ), thus, this factor alone will result in a fasterdissolution rate as described by Noyes–Whitney. 13 In addition,the Prandtl equation shows that the drug nanocrystals showeddecreased diffusional distance “ h ”. This further enhances thedissolutionrate.Finally,theconcentrationgradient( C s − C x )isalso of high importance. There are reports that drug nanocrys-tals have shown increased saturation/thermodynamic solubil-ity ( C s ). This can be explained by the Ostwald–Freundlichequation 14 and by the Kelvin equation. 15 It is still not clear to what extend the saturation solubilitycan be increased solely as a function of particle size. Most prob-ably theincreased solubilityof drugnanocrystals is acombinedeffect of nanosized drug particles and solid-state effects causedby the particle fractionation during the process. A number of authors have reported improvement from a 10% increase in Shah, Murdande, and Dave, JOURNAL OF PHARMACEUTICAL SCIENCES DOI 10.1002/jps.24694  REVIEW  3 Table 1.  Advantages of Nanocrystals in Different Route of  AdministrationRoute AdvantagesOral   Increase bioavailability     Decrease in fed/fast variations     Increase rate of absorption; decrease in  T  max and increase in  C max     Quick and easy to formulateParenteral    About 100% bioavailability can be achieved if given as an IV formulation     Targeting drug delivery      Avoidance of organic solvent, surfactants, pHextremesPulmonary   Used in nebulizer as a liquid solution or drypowder      A single drop can contain many nanoparticles     Increase the concentration and or loading of nanocrystalline dispersion saturation solubility to several folds using differentapproaches. 16–20 Below are the established equations to de-scribe nanocrystals and their physicochemical properties. Advantages of nanocrystals over conventional and specialdrug delivery systems:1. Because of high surface enlargement factor in nanocrys-tals, there is an increase in the dissolution rate as wellasamodestincreaseinsaturationsolubilityascomparedwith micronized particles.2. With a size range in nanometers, it can be injected as aIV to get 100% bioavailability.3. Dose reduction and patient compliance.4. Lessen or eliminate the food effect on bioavailability.5. Targeted drug delivery either by transcellular or intra-cellular uptake.6. Molecule can be delivered via a required route with easein scale up.This review focuses on the various established approachesfor the formulation of nanocrystals, the different published an-alytical methods applied for thermodynamic solubility deter-mination, assessment of dissolution properties and dissolutionrate enhancement upon nanosizing, the effect on pharmacoki-netic (PK) properties such as bioavailability, the area undercurve (AUC), and the half-life due to size reduction as well asfuture research opportunities. FORMULATION APPROACHES FOR NANOCRYSTALS Before the first top-down processes were developed (i.e., tech-niques reducing the size of larger crystals by means of attritionforces), nanosized drug particles were produced using a sim-ple precipitation approach known as solvent–anti-solvent ad-dition technique. It is also referred as one of the “bottom-up”approaches. However, it is often difficult to control the particlegrowth/crystal growth using this technique as well as to scaleup by maintaining all the parameters constant. Therefore, itwas suggested to perform the precipitation step in conjunctionwith immediate lyophilization, or spray-drying, in order to re-duce the risk of crystal growth. Top-Down Approach There are two basic approaches which are well established forthe formulation of nanocrystals:1. Top down: Involves the mechanical reduction of the par-ticle size by wet media milling or high-pressure homoge-nization (HPH).2. Bottomup:Involvesthegenerationofnanosizedparticlesfrom dissolved molecules by means of precipitation. 9 Top-down methods can be further divided in to twoapproaches—homogenization and attrition wet media milling. Attrition Wet Media Milling ThistechnologywasdevelopedatthePharmaceuticalResearchDivision of Eastman Kodak (Sterling Winthrop, Inc.), whichwas set-up as NanoSystems LLC and later acquired by Elan. An active drug substance is dispersed with an aqueous solutionin which the stabilizers were pre-dissolved. As the surface of nanocrystals is highly cohesive and has high surface energy,it should be stabilized by a single or mixture of stabilizers.Stabilizers can be ionic or stearic and can be used as a singleand/or in a combination of polymeric as well as surfactant sta-bilizers. This solution is poured in the grinding chamber along with spherical beads/balls while the beads are rotated at veryhigh speed. It is believed that because of the attrition betweenmolecules’ surface and surface of the beads, particle size reduc-tion occurs; the beads/balls serving as a milling media. Beadsare available in various sizes and are of different materials,but generally are made of glass, zirconium oxide, or polymericmaterial. The type of material the beads are made of is a crit-ical factor as they can interact with the active drug substance.There is a fair chance that an impurity related to the materialof beads may contaminate the final product. Yttrium-stabilizedzirconium oxide is the most widely used type of bead by ma- jor pharmaceutical companies because in most cases, it doesnot interact with active drug substances. Although expensive,these beads are the best alternative to avoiding impurities inthe final formulation. 21 The size of the beads has a direct relationship with the de-sired particle size range in the formulation of nanocrystals. 22 The usual duration for conventional milling using overheadstirring is somewhere between 3 and 12 h. Certainly, these pa-rameters can change from molecule to molecule. Milling shouldbe stopped once the desired particle size range is achieved. Therotational speed of the milling media is also a critical parame-ter. With the too slow speed, the beads cannot rotate efficientlyand milling cannot be performed accurately, and with the toofast speed, the evenly rotating balls may remain at the uppersurface of the media and milling does not take place. With asystematic study by trial and error the formulator selects thestabilizers, as well as other milling parameters and optimizesthem in order to achieve the desired particle size range andstability. The final product characteristics can vary, depend-ing on the amount of beads, the ratio of active drug substanceto the amount of beads, the ratio of concentrations of activesubstance to the stabilizer, milling time, milling temperatureas well as milling duration. 23 This method is simple, inexpen-sive, and easily scalable. The only drawback associated withthis technology is the contamination related to the beading  DOI 10.1002/jps.24694 Shah, Murdande, and Dave, JOURNAL OF PHARMACEUTICAL SCIENCES  4  REVIEW material. That aside, several products have successfullyreached the commercial level using this technology. High-Pressure Homogenization There are several established methods for the formulation of nanocrystalsusingthehomogenizationapproach.Themicroflu-idization technology (Insoluble Drug Delivery-Particles IDD-P TM Technology), Dissocubes R   technology, and Nanopure R  technology are examples of the methods that fall under thiscategory. Microfluidizers are known as high shear fluid pro-cessors that are unique in their ability to achieve monomodalparticlesizereduction.Itreducesparticlesizebyafrontalcolli-sion of fluid streams under pressure of up to 1700 bar. 24  At veryhigh pressure, collision and cavitation occur. The major draw-back associated with this method is that it requires at least50–75 cycles to achieve the desired nanometer size range. Thismakes the method more tedious and relatively more time con-suming as compared to milling. Dissocubes R   technology workswith piston gap homogenizer, which was developed by Mullerand his colleagues. In this method, a crude aqueous suspensionof active drug substance and stabilizer is forced through a tinyhole, which can reach a pressure of up to 4000 bar. The widthof the homogenization gap is adjustable, which is typically inthe micrometer range.Compared with wet media ball milling, there are fewerchancestogenerateimpuritieswithHPH.Thenegativeaspectsof using this method are cavitation, which causes mechanicalwear, as well as noise, although fragmentation is a beneficialeffect associated with cavitation. The main source of impuritycomes from the wearing out of equipment parts. Almost all ma-chinepartsaremadeofstainlesssteel,whichleadstoaverylowimpurity level when the nanosuspension is prepared using theHPH.KrauseandMuller 25 carriedoutacomparativestudyandobserved a negligible amount of iron impurities in the nanosus-pension formulated with 20 cycles at 1500 bar. Wear and tearoccurs only when very hard material is processed through thepiston gap. Using stainless steel material can also lead to wearand tear as the new type of homogenization valves used todayare made of ceramic tips which are able to withstand the harshprocessingconditions. 26 Homogenizersvaryinsizefromasmallscale to large scale production. 27 Many research studies havereported minimal growth of microorganisms as a result of theHPH process. 28 These improve the shelf life of the nanosuspen-sion and avoid the need for further studies that are requiredif it is administered orally. However, it is not a rule of thumb,the HPH is generally used for relatively soft material and beadmedia mill is used for relatively harder or harsh material. Combinative Approach In order to proceed with both the top down technology (wet me-diamilling,HPH)micronizedpowderisrequiredasthestarting material, which leads to a long process time. In order to over-come this drawback, a combinative formulation approach wasdeveloped. The combinative approach was first developed andintroducedbyBaxterInc.asNanoedge TM technology.Todayfivecombinative methods have been successfully developed.1. Nanoedge TM —microprecipitation + HPH2. H69—microprecipitation immediately followed by HPH(minimization of time between two steps in order to pro-duce even smaller crystals)3. H42—drug pre-treatment by means of spray-drying fol-lowed by standard HPH4. H96—Freeze drying combination with HPH5. CT—Media milling followed by HPHInthemicroprecipitationstage,thedrugisusuallydissolvedin a suitable organic solvent that is miscible with water. Thedrug solution is then added to an aqueous solution in whichstabilizers have been pre-dissolved. The drug solution is addedin a controlled manner to prevent inadequate crystal growth. After the microprecipitation step, precipitates are convertedinto more stable crystals in the nanometer size range with thehelp of top down technologies (i.e., HPH, media milling, andsonication). The amount of residual content in the final prod-uct is the major concern while using a combinational approachduring scale up. The presence of organic solvent can alter thephysicochemical properties of the active drug substance. 29 Itmay also be responsible for the Ostwald’s ripening. To preventthis from happening, an alternative method was developed bySalazar et al. 21 known as H 42 and H 96 technology. H42 usesthe spray drying of the microprecipitated solution that was de- veloped with the bottom-up approach, and then followed byHPH. In the case of H96, it employs the freeze drying of the mi-croprecipitated solution, followed by a top-down approach. In-deed, on the one hand, this method has more advantages thanany single step conventional method, but on the other hand,any additional steps in the procedure require more careful andmore extensive research, and control of additional parameters,which will increase the cost of the end product development. Todate, no product has been developed and marketed using thistechnology, but research papers have been published for theformulation or production of nanocrystals using the combina-tiveapproach.Amongthese,thetop-downapproachesaremoreconvenientbecauseoftheeaseofbeingabletogoverntheparti-cle size range as well as the ease of scaling up. Because of thesebenefits, several products have been successfully launched tothe commercial level. Bottom-Up Approach This method is also known as the precipitation approach.Hydrosols 30 and Nanomorph 31 techniques are examples of thebottom-up approach. The particles generated by Nanomorphtechnology are amorphous in nature, which give an advantageof both a higher supersaturation and a higher dissolution rate.It is well known that amorphous systems are high energy sys-tems;therefore,becauseoftheirhighrateofcrystallization,un-controllablecrystalgrowthoccurs,whichleadstoareductioninsolubilityandeventually,reductioninbioavailability.Althoughboth technologies are scalable, they require the control of dif-ferent parameters, such as temperature and the stoichiometryof the solute, solvent, and the stabilizer. UNDERSTANDING SOLUBILITY BEHAVIOR ANDMETHODS OF DETERMINATION Several research papers have discussed the impact of solubilityand particle size on the PK performance of nanocrystals. Someoftheliteraturehasreportedthatthegenerationofsurfacecur- vature and crystal defects on the particle surface have an enor-mous impact on its solubility behavior. Another possible causemight be the development of high energy surfaces through Shah, Murdande, and Dave, JOURNAL OF PHARMACEUTICAL SCIENCES DOI 10.1002/jps.24694  REVIEW  5 attrition during particle size reduction. According to the litera-ture,solubilitymayrangefromone-foldtoseveralfold,basedonparticle size. 17–19 Bioavailability enhancement associated withnanocrystalline API is attributed to an increase in the dissolu-tion rate because of the enlargement of SA and some increasein solubility based on particle size. This solubility enhance-ment should be in fair agreement with what would be expectedbased on the Ostwald–Freundlich equation. A change in solu-bility is more significant when particle size is reduced to below100nm,whichcanalsobedescribedbytheOstwald–Freundlichequation. Rapid dissolution associated with a nanoparticulatesystem is clear evidence of a generation of transient super sat-uration of a solution compared with the bulk solubility of astable crystal form. In the case of crystalline nanoparticles, thedegree of supersaturation is low compared with high energyamorphous solids, as particle size has limited impact on satu-ration solubility.Determining accurate solubility is vital to characterize theeffectiveness of the formulation. There are several challengesassociated with the accurate determination of solubility of anyformulation, as it varies case by case. Accurate measurementis significantly more complicated in the case of nanoparticulatesystems, as they have the tendency to remain in suspendedform in the solution after using conventional approaches. It isalmost impossible to visualize the presence of nanoparticles inthefiltratewiththenakedeye.Theintrinsicsolubilityofpoorlysoluble compounds is extremely low in number; therefore, thepresenceofacoupleofundissolvedparticlescanleadtoasignif-icant error in measurement. While reviewing the literature fordetermining solubility by a separation-based method, we havefound the absence of a validated universal method for accuratesolubility determination. This makes it even more challenging whendealingwithparticlesizeinthenanometerrange,ascom-pared with the micronized or bulk particles. The following arethegeneralchallengesassociatedwithsolubilitydeterminationof the nanoparticulate system.1. No standard method is available in the literature for sol-ubility determination,2. Difficulty in separation of the dissolved and undissolvednanocrystals/particles because of smaller size.3. Confirmation that equilibrium is attained or not.4. Reproducibility of results.5. Validation of method for accuracy.In addition to the above challenges, one also has to considerother process parameters which vary with the physicochemicalpropertiesoftheactivedrugsubstanceforsolubilitydetermina-tion. For instance, if the API is weakly acidic or basic, then thepHofthesolutionplaysanimportantrole.Itisdifficulttodeter-mine whether or not equilibrium is attained in this particularcase. Several researches have published different approachesfor the solubility determination of nanocrystals. Although nu-merousmethodsfortheseparationofdissolvedandundissolvednanoparticleshavebeenreportedintheliterature,thesearethemost common approaches used described in Figure 1. An aque-ous solubility determination by separation-based approach iswidely accepted, has been used in industry and academia formany decades, and is the most convenient way to determinesolubility. Typically, it is a two-step process: initially, an excessamount of drug is dispersed in an aqueous or buffer solution.The equilibrium is established by shaking or stirring the solu-tion at a specific rpm for a specific time and temperature, atwhich we want to determine the solubility. Usually the sam-ples are withdrawn after 24 and 48 h. Samples were either cen-trifuged or filtered from syringe filters. A sample analysis wasperformed using the HPLC and UV. In the case of crystallinenanoparticles, the research articles listed in the Table 2 havereportedthesolubilitydeterminationdatafornanosuspensionsand nanocrystals by utilizing a separation-based approach astheir primary method for solubility determination. The mostcommonly reported approaches for solubility determination of nanoparticles are by shake-flask method at a specific temper-ature. Most of them have overestimated the thermodynamicsolubility associated with nanocrystals, which is why it is im-portant to consider some additional factors during solubilitydetermination when particle size is reduced to nano from mi-cron range. The selection of appropriate pore size filters withrespect to the particle size of crystals, and the selection of anappropriate spectroscopic analytical method, is the key factorthatneedstobetakenintoconsiderationforaccuratesolubilitydetermination of crystalline nanoparticles.Bernard Van Eerdenbrugh reported that the UV spectra is areliable tool to determine the concentration of micronized par-ticles, however, it is not a reliable tool for the determinationof the concentration of nanosuspensions, as it is overestimat-ing the actual solubility data. With particles in the nanome-ter range, they itself absorbs the UV light. Therefore, the ab-sorbance data are the mixture of the dissolved and undissolvednanosized particles. 32 Today, the measurement of the dissolveddrug concentration using an  in situ  UV probe is the preferrednoninvasive method because of its sophistication in terms of contingency and its ability to record data from the start of dis-solution. However, absorption of light from particles is size de-pendent and it is having a great influence on smaller particles.With felodipine as a model drug, an observation has been madethat both nanoparticulates of felodipine and free felodipine inthe solution absorb light in a similar way, which results in anoverestimation of dissolved concentration than what was actu-ally dissolved. 33 The results were also dramatic, even for thesecond derivative of UV spectra. Moreover, the generation of nanoparticles occurs when working with nanosuspensions orsupersaturated systems, so caution should be taken.The solubility associated with crystalline nanoparticles ismoderately higher (10%–15%) 16 compared with what is re-ported in Table 2. 34–44 In the case of indomethacin, the reportedsolubility enhancement was nearly twofold higher. The same istrue in the case of oridonin, 36 reccardin D, 38 and simvastatin 39 wherereportedsolubilitywassubstantiallyhigherascomparedwith bulk crystal solubility. One possible reason behind thismisleading data may be the use of an inappropriate separating method and/or analytical method. Nanoparticles with an aver-age size of 200–400 nm can easily pass through 0.22 or 0.45  : mpore sized filters. Determining the concentration of such a fil-tered solution using UV leads to a further over-estimation of actual data because of the mixture of absorbance of both theundissolved and dissolved particles. Moreover, centrifugationat moderate speed of about 10,000–30,000 rpm is not suffi-cient to suspend particles in the nanometer range, therefore,the resultant supernatant contains a mixture of dissolved andundissolved particles. It is noticeable that care should be takenin choosing syringe filters for appropriate pore size. Juene-mann et al. 45 were able to show in their study a differentiation DOI 10.1002/jps.24694 Shah, Murdande, and Dave, JOURNAL OF PHARMACEUTICAL SCIENCES
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