the therapeutic action of many newly developed 
 active pharmaceutical ingredients ( apis ) or drug molecules is limited 
 to low aqueous solubility , and they belong therefore to the biopharmaceutics 
 classification system ( bcs ) class ii or iv . enhanced solubility may be achieved by various approaches ; for instance , 
 a reduction in particle size promotes dissolution and thus systemic 
 absorption . however , precaution needs 
 to be taken as api nanoparticles are developed as these are able diffusing 
 through cell barriers causing cell malfunctions . while amorphous solid states 
 are favorable in terms of solubility and dissolution rate , they often 
 lack on long time stability , resulting in undesired crystallization 
 on storage . furthermore , 
 apis are able to pack in various different crystalline arrangements 
 with each polymorph having a different long time stability and physical - chemical and therapeutic properties . api 
 loaded surfaces provide an alternative for systemic absorption through 
 topical or buccal routes from patches or 
 nanoparticle surfaces . surfaces made from 
 poly(lactic - co - glycolic ) acid ( plga ) or cellulose aid in the formulation 
 and help to transport the api to the specific side of actions ( i.e. , 
 drug targeting ) . anyway , the usage of 
 such approaches requires deeper knowledge of api  surface interactions 
 for optimized drug formulations . for instance , at surfaces organic 
 molecule deposition from solutions may result in altered polymorphic 
 structures or morphologies compared to bulk crystallization within 
 solutions . in this study the formation 
 of thin layers of a model api at a solid , flat glass substrate is 
 investigated . such a model system provides the possibility to study 
 interactions with various surface sensitive methods like atomic force 
 microscope ( afm ) and gracing incidence x - ray diffraction . further 
 this simple model allows gaining information on important parameters 
 useful for application relevant to other systems including patches 
 or colloidal particles prepared in solutions or spray drying . the 
 api used is 5,5-diphenyl-2,4-imidazolidinedione ( phenytoin ) . while 
 phenytoin is an anticonvulsive , antiepileptic , and antiarrhythmic 
 drug and is typically used in solid oral dosage forms ( i.e. , capsules 
 and chewable tablets ) as well as in parenteral formulations , it is 
 chosen for this study as it is also known to be isomorphic . this means 
 that the molecules assemble in a unique crystalline phase which makes 
 it a perfect candidate for this study . often changes in the preparation 
 route cause crystallization in other polymorphic structures which 
 hardens the understanding of the film formation as other polymorphic 
 structures results in other morphologies . within this study films are prepared by a spin - casting technique which is a fast and reproducible preparation 
 procedure . the variation of the api amount in the solutions and spin 
 parameter will show differences in the phenytoin assembling at a silica 
 surface . afm and diffraction measurements are used to study the morphological 
 and crystallographic properties allowing elucidating changes in the 
 dissolution behavior . phenytoin 
 was purchased from sigma aldrich ( sigma - aldrich , munich , germany ) 
 and used without further treatment . acetone ( 96% ) was also purchased 
 from sigma aldrich ( sigma - aldrich , munich , germany ) in spectroscopic 
 grade . standard microscopy glass slides ( roth , karlsruhe , germany ) 
 were cut in 2.5  2.5 cm pieces and cleaned in ethanol , 
 acetone , and a 0.1 m naoh solution and dried under a nitrogen stream . this results in a hydrophilic surface with a water contact angle of 
 35. acetone and phenytoin solutions have contact angles of < 20 ; 
 the low surface tension of acetone results in the liquid spreading 
 along the surface . the 
 spin coating experiments were performed by dropping 200 l of 
 various concentrated acetone solutions onto the glass slides and subsequently 
 rotated at 25 rounds per second ( rps ) for 30 s around its surface 
 normal . all samples were stored under a vacuum of 10 mbar for 2 h at ambient temperatures prior the experiments to reduce 
 residuals of the solvent . tap190-al cantilevers ( budgetsensors , 
 sofia , bulgaria ) were used for all experiments . specular x - ray diffraction experiments 
 were performed with a siemens 500d diffractometer in bragg the copper radiation ( wavelength  = 0.154 nm ) 
 was narrowed with primary and secondary side slit systems . the diffracted 
 intensity was guided toward a graphite monochromator and collected 
 by a scintillation counter . the angular measurement ( 2 ) is 
 represented in the scattering vector ( qz ) notation which calculates as qz = 4 sin()/. grazing incidence x - ray diffraction ( gixd ) 
 experiments were performed with a modified lab based bruker d8 discover . the copper radiation is parallelized via a goebell 
 mirror and defined by parallel plate collimators . the diffracted beam is led trough a collimator system and is collected by a vantech 1d 
 detector . the apparent solubility 
 ( cs ) of bulk phenytoin and from spin - coated 
 samples was evaluated , and the content uniformity of prepared spin - coated 
 samples was determined using standard routines according to european 
 pharmacopoeia v 7.0 . dissolution experiments , that is , the amount 
 of api dissolved over time of both samples , were conducted on a horizontal 
 shaker ( ika yellow line rs 10 control , ika - werke gmbh & co. kg , 
 germany ) at 200 rpm and a temperature of 25 c . the dissolution 
 experiments were setup by adding a phenytoin coated glass slide ( i.e. , 
 94.02  8.16 g of phenytoin ) or 4.7 mg of bulk material 
 into dissolution vessels , and 20 ml ( spin - coated samples ) or 1000 
 ml ( bulk material ) , respectively , of milli - q - water was added . an aliquot 
 of 1 ml was withdrawn after defined times over 6 h. the concentration 
 was determined by uv  vis adsorption measurement at a wavelength 
 of 220 nm using a nanophotometer ( implen , munich , germany ) and standard 
 quartz cuvettes ( hellma , mllheim , germany ) . for statistics , four samples of each kind were investigated , and the standard deviation 
 was elucidated . the variation 
 of phenytoin concentration within acetone solution results in the 
 formation of various morphologies at a glass surface as the solutions 
 are spin coated at a spin speed of 25 rps . in figure 1 afm height images of films deposited from 0.05 to 1.5 wt 
 % acetonic solutions are shown . at the lowest concentration of 0.05 
 wt % separated islands of phenytoin the islands ( bright 
 areas in the image ) consist of small spot like structures which are 
 connected by flat areas . a mean thickness of about 30 nm no material 
 could be identified ; thus a layer that fully covers the substrate 
 is absent . at a slightly increased concentration of 0.1 wt % the particles have 
 a height of about 70 nm and are a result of the solution favoring 
 dewetting from the silica surface . besides these particles elongated 
 needle like structures are visible which correspond to the typical 
 structure observed on slow solvent removal ( data will be shown elsewhere ) . these needles have an extension of up to 6 m . a height of 40 
 nm shows that these structures are significantly lower compared to 
 the drop like particles , suggesting that this morphology stronger 
 interacts with the surface ; thus a rod - like growth along the surface 
 is present . afm height images of phenytoin films spin coated from 0.05 wt % 
 ( a ) , 0.1 wt % ( b ) , 0.5 wt % ( c ) , 1 wt % ( d ) , and 1.5 wt % ( e1 ) . the 
 color scale is chosen individually for clarity . increasing the concentration further results in a phenytoin a width of 3.3 m and height of 240 nm can be deduced from the 
 afm image ( figure 1c ) . at the connection points 
 of these structures larger islands form . such structures are typical 
 for materials trying to dewet the surface , but as sufficient material 
 is present interconnections develop during drying . at a concentration 
 of 1 wt % the gaps in between the elongated structures start to fill 
 resulting in a 90 nm thick film with nearly full coverage but with 
 remaining holes ( see figure 1d ) . however , increasing 
 the concentration to 1.5 wt % results in a film that entirely covers 
 the glass substrate ( see figure 1e1 ) . surprisingly , the afm height image reveals a tree - ring like structure 
 with concentric rings forming around a common center . a high resolution 
 image reveals that this tree - like structures are a result of small 
 particles packing together ( figure 1e2 ) ; thus the tree - like rings form on account of particle packing during 
 solvent removal . furthermore the results suggest that various phenytoin 
 nuclei rapidly form during the spinning process , which then assemble 
 in this observed tree - like structure . all samples shown in figure 1 were prepared at the same spin speed of 25 rps . 
 at low concentrations dewetting structures are observed . typically , 
 such structures are a result of the molecules at the api  glass 
 interface disfavoring their contact ; that 
 is , the adhesive forces are smaller than the cohesive forces which 
 results from the difference in their polar and apolar interaction 
 sides . phenytoin is a highly hydrophobic molecule , while glass is 
 hydrophilic which results in a disjoining force and thus in dewetting . within very thin films the interface is the 
 dominating factor . anyway , as the film thickness increases , the balance 
 of short - range ( e.g. , double layer forces ) and long - range forces ( e.g. , 
 van der waals forces ) is changed . as a result , the film stabilizes , 
 and a homogeneous layer without holes results . in the case of phenytoin deposited from a 1.5 wt % acetone 
 solution at 25 rps , a fully closed layer with a thickness of 121 nm 
 forms . the variation of the solution concentration has a drastic 
 effect on the film morphology . anyway , the variation of the spin speed 
 also strongly affects the morphology . in figure 2 the afm images of phenytoin thin films prepared by various spin 
 speeds from the same 1.5 wt % aceton solution are shown . at a spin 
 speed of 10 rps the morphology shows again various tree - ring like structures with 
 centers around the middle and in the right up corner of the image 
 ( see figure 2a ) . compared to the structure 
 observed at 25 rps the number of rings and the packing density are 
 increased ( compare figure 1e and figure 2a).the corresponding high resolution image reveals 
 that the structure results from particles packing closely together 
 but with the particle size being increased compared to samples spin - coated 
 at 25 rps . the situation remains similar for samples which are prepared 
 at 50 rps ( see figure 2b ) , but the particle 
 size is reduced compared to the other two samples . afm height images of 
 phenytoin thin films spin - cast at rotation speeds of 10 rps ( a ) , 50 
 rps ( b ) , and 100 rps ( c ) . spin - casting of the film at a rotation speed of 100 rps results 
 in a strong deviation of the morphology ( see figure 2c ) . other than the previous films , clear dewetting structures 
 with large areas remaining uncovered are present ( e.g. , left top corner ) . in addition small holes in the film are noticeable as dark spots within 
 figure 2c and c1 . the morphology 
 of the particles is slightly more elongated compared to the sample 
 prepared at a spin speed of 50 rps . for a quantitative evaluation 
 of the surface properties on the variation of the rotation speed , 
 the layer thickness ( d ) , the root - mean - square roughness 
 ( rms ) , and the power spectral density ( psd ) were 
 evaluated . the data are summarized in table 1 . for the film prepared at a spin speed of 10 rps d = 159 nm and rms = 17.5 nm as the 
 spin speed is increased to 25 rps , d reduces to 121 
 nm as well as the rms reduces to 16.2 nm . for the 
 50 and 100 rps samples d = 54 and 45 nm , respectively , sp - sp , 
 spin speed ; d , layer thickness ; rms , root - mean - square roughness ; c , correlation length . the power spectral density 
 of the various samples , calculated from figure 2a12c1 , are summarized 
 in figure 3 . within such an evaluation common 
 distances on a surface are extractable . for the sample prepared at 10 rps a high spectral density is observed 
 for small wave vectors ( k ) . as k is increased , the density drops from the plateau and reaches the 
 background level above 0.2 nm . for the evaluation 
 of common distances , linear regression fits in the plateau , and the 
 linear decreasing regions are performed ( lines in figure 3 ) . the intersection point of the lines typically 
 describes a correlation length ( c ) ( or common distance ) , 
 which calculates as c = 2/k . the 10 rps sample reveals a real space correlation of 570 nm which 
 agrees well with the mean particle sizes observed in figure 2a1 . the same evaluation of the 25 rps 
 and 50 rps samples reveals a very similar behavior but with the correlation 
  drop off  shifting to larger wave vectors ; a real space 
 correlation length of 398 and 363 nm is obtained for the 25 and 50 
 rps , respectively . thus the increase in spin speed does not only decrease 
 the layer thickness but also decreases the particle size . the first is 
 at low k = 0.0028 nm ( corresponding 
 to a real space distance of 2.2 m ) , and a second is present 
 at a higher wavevector of 0.021 nm ( real space 
 distance of 311 nm ) . inspecting the afm image shows that the large 
 correlation length is due to the holes within the sample ; that is , 
 the holes have a mean separation of 2.2 m . the 311 nm correlation 
 is due to common particle size which are smaller compared to the previous 
 samples . power spectral density spectra for samples prepared from the 1.5 
 wt % solution deposited at various spin speeds . the determined particle sizes for all samples have lateral 
 extensions which are larger than the film height . from this follows 
 that the films consist of small cylinder like particles with an aspect 
 ratio ( lateral size / film thickness ) of 3.5 for the thickest film and 
 increases to 6.6 for the thinnest film . this means that particles 
 forming during the spin coating process become more  flake 
 like  as the spin speed is increased . the afm images 
 reveal the formation of particular films on the spin coating process . typically , spinning at a low speed means that the system has 
 more time to assemble until the solvent is evaporated . during the 
 solvent evaporation , supersaturation takes place , resulting in phenytoin 
 nucleation , and these initial nuclei grow into larger crystallites 
 until the entire acetone is vanished from the sample . at larger rotation the layer thickness is reduced and is composed of an increased number 
 but smaller crystallites compared to  slower prepared  
 samples . at the fastest speed investigated , that is , 100 rps , the 
 particles are not able to entirely wet the surface . often liquids 
 form dewetting structures at solid surfaces . these structures may 
 assist in the movement of already formed particles as well as the 
 dissolved molecules along certain channels within the surface ; thus 
 the observed dewetting structures form . for the characterization 
 of the crystalline structure of the phenytoin films , x - ray diffraction 
 experiments are performed , and the results for the 1.5 wt % at 25 
 rps spin coated samples are shown in figure 4 , for example . to our knowledge there exists only one polymorphic 
 modification of phenytoin in literature ; the phenytoin molecules pack in a tetragonal unit cell with a = 0.62 nm , b = 1.36 nm , and c = 1.55 nm which reveal a calculated powder pattern demonstrated 
 in figure 4 . within the experimental scan of 
 the thin film , only one peak at 8.09 ( the 
 broad amorphous hump results from the underlying glass substrate ) . 
 within a specular scan , only net planes which are parallel to the 
 substrate surface are detectable ; thus it follows that the sample 
 shows a preferred alignment ( texture ) with respect of the surface . anyway , gixd measurements result in a slightly 
 different conclusion ( see figure 5a , b ) . in such a scan net planes which are parallel ( or close to ) to the surface 
 normal are investigated . the gixd pattern 
 reveals high intensity spots ( highlighted by white x s in figure 3b ) and are a result of bragg reflection of certain 
 miller s indices ( hkl s ) . using the 
 information of the unit cell shows that these hkl s are a result of phenytoin assembling in a 001 texture in 
 accordance with the specular scan . however , ring - like structures are 
 also noted . such rings are a result of random orientations of the 
 crystallites or powder like behavior ; that is , within an ideal powder , 
 no preferred orientation exists . from this follows that fractions 
 of the crystallites adapt a random conformation with respect of the 
 surface . as the film is thin ( only 121 nm ) , the amount of random particles 
 is probably very low , which causes an absence of bragg peaks in the 
 specular scan . within a powder sample all bragg reflections which 
 have sufficient intensity should be visible , as observed for the as - delivered 
 powder sample investigated in figure 4 . specular x - ray 
 diffraction scan of the phenytoin sample prepared from 1.5 wt % actone 
 solution at a spin speed of 25 rps ( top ) , experimental powder diffraction 
 measurement of the as - delivered powder ( middle ) , and the calculation 
 of an ideal powder ( bottom ) . gixd pattern of the phenytoin sample prepared from 1.5 wt % solution 
 and spin coated at 25 rps ( a ) . dashed box indicates the area over 
 which the pattern is integrated to generate a line scan ( b ) . gixd is a very surface sensitive technique allowing 
 order and disorder within films as thin as monolayers to be determined . as 
 there is no indication of an amorphous hump within the gixd pattern , 
 this means that the film consists solely of crystalline phenytoin . in figure 5c the packing of the molecules 
 viewed along the crystal a - axis is shown . in such 
 a representation the 001 net - planes are parallel to the crystal b - axis , or in other words the a- and b - axis are in contact with the glass surface . all 
 rings are twisted with respect to each other , whereby the imidazolidin 
 ring runs along the crystal a - axis . furthermore the 
 imidazolidin ring adapts a position at which the terminal oxygen is 
 in contact with the glass surface within a 001 textured growth . as 
 glass surfaces typically have highly polar and/or hydrogen bonding 
 sites , this contact is favored , and as a result the 001 orientation 
 is preferentially obtained . anyway , the additional powder characteristic 
 is most likely a consequence of fast removal of acetone during the 
 spin - casting process ; the api concentration rapidly increases resulting 
 in the formation of various nuclei simultaneously . for nuclei close 
 to the surface interaction further off the surface an adaption with respect 
 of the surface is not present ; thus the  bulk crystalline 
 particles adapt a random orientation . comparing the gixd line 
 scans pattern of the thin film sample with the powder pattern of the 
 as - delivered material reveals an excellent agreement of the peak positions 
 ( compare figure 4 middle and figure 5b ) . variations in the peak heights are a result 
 from varying texture being present within both samples resulting in 
 enhancing or decreasing bragg peak intensities . additionally , these 
 results are in excellent agreement with a calculated powder pattern 
 ( figure 4 bottom ) . from this follows that the preparation route via spin coating does 
 not influence the crystallographic properties of phenytoin , that is , 
 an incorporation of acetone within the thin film is very unlikely , 
 and the same polymorph forms . for the evaluation of the solubility 
 properties of phenytoin deposited on the glass surface dissolution 
 profiles are determined , i.e. the increase in solute concentration 
 over time ( see figure 6 ) . milli - q water was 
 chosen as dissolution media as it minimizes the impact of surface 
 affine species within other dissolution media ( e.g. , salts ) onto the 
 particle removal from the surface . at a short period of time ( 5 min ) 
 a concentration of 1.5  0.1 g / ml is already obtained . 
 as time progresses the concentration increases linearly and reaches 
 a value of 3.1  0.1 g / ml after 30 min . at this point it 
 took another five and a half hours to reach a value of 3.5  
 0.3 g / ml . phenytoin concentration as a function of time for thin 
 films samples and the as - purchased powder . additionally , dissolution studies of bulk phenytoin were 
 conducted for sake of classification , that is , if the spinning process 
 results in improved dissolution properties . the dissolution studies 
 were performed under same conditions ( i.e. , same amount of api relative 
 to dissolution - media volume , temperature , same apparatus , same parameters ) 
 to make results comparable . as shown in figure 6 ( bottom curve ) , api release of bulk phenytoin is noticeable after 
 30 min at which a concentration of 0.5  0.1 g / ml is determined . ( api concentrations prior 30 min were under the detection limit of 
 the experimental setup . ) from this point , a linear increase in drug 
 concentration is observed , and at 1 h a concentration of 1.3  
 0.2 g / ml is reached . after 1 h the increase in api concentration 
 is slowed down . at 6 h a solution concentration of 2.5  0.5 
 g / ml is measured . within the dissolution experiments the amount of phenytoin dissolved from the thin spin - cast sample is 
 significantly higher at all times compared to the bulk powder sample . furthermore , the spin - cast sample reveals a rapid dissolution at the 
 very beginning with most of the phenytoin being dissolved . in contrast 
 the dissolution of the bulk material after this time was just initiated . basically , thin films of phenytoin crystals exhibit an improved solubility 
 behavior with higher and faster dissolution rate due to higher specific 
 surface area of the smaller particles being available for dissolution 
 media . the bulk phenytoin shows a particle size distribution of d0.9 = 25.0 m , d0.5 = 14.1 m , and a d0.1 = 7.7 m whereby the afm height images reveal crystal sizes 
 around 400 nm . it was observed that twice as much phenytoin 
 could be dissolved when prepared as thin film ( i.e. , 23.6  0.6 
 g / ml ) compared to untreated bulk phenytoin ( i.e.,11.5  
 0.5 g / ml ) . by varying the spin coating 
 process the film appearance as well as the local morphology ( shape 
 and size ) of phenytoin could be manipulated . the results show that 
 the api crystallizes fast on the removal of the solvent and particles 
 form whereby the size can be manipulated by the spin speed . furthermore 
 the variation of solution concentration reveals morphologies that 
 varied from separated islands to extended dewetting structures and 
 finally fully closed layers . the dissolution properties of films prepared 
 by spin coating technique are significantly improved compared to those 
 of the bulk powder . this gives confidence that the other system including 
 multilayer application forms may be improved as well by the usage 
 of this approach .
given 
 the increasing number of poorly soluble and thus poorly bioavailable 
 active pharmaceutical materials , there is a demand for innovative 
 formulation platforms for such molecules . 
 thus a focus on enhancing 
 dissolution properties of poorly soluble drugs exists . within this 
 study , 
 the spin coating of acetone solutions containing 5,5-diphenyl-2,4-imidazolidinedione 
 ( phenytoin ) in various concentrations is evaluated . 
 the results reveal 
 strong variations of the morphology of deposited phenytoin crystals 
 at silica surfaces . 
 individual separated particles are obtained on 
 low phenytoin concentrations , and closely packed particular films 
 form when the concentration is increased . 
 as the material is isomorphic , 
 these various morphologies have the same crystalline structure . 
 dissolution 
 experiments reveal that both the apparent maximum solubility and as 
 the dissolution rate are strongly enhanced compared to bulk powder , 
 suggesting that formulation based on this preparative technique will 
 allow overcoming the low solubility problematic for a variety of drugs .