defined thin film preparation of organic 
 molecules on solid surfaces 
 is of great importance in a variety of fields , including pharmaceutics , organic electronics , and colloid science , among many more . typically 
 the preparation method and the surface properties of the substrate 
 have a decisive impact on the morphology and the polymorph forming 
 with each having specific physical and chemical properties . for instance , 
 small particles can be obtained from phenytoin sitting on a solid 
 silica surface via a spin - casting process , which results in an increased 
 solubility and dissolution rate , both being strongly enhanced compared 
 to the bulk material . another example 
 is the achievement of surface - mediated polymorphic structures by changing 
 the preparation condition within alkyl - terminated terthiophene thin 
 films . small crystals may also be obtained via atomic force 
 microscopy , which initiates crystallization during scanning . within pharmaceutical applications , the 
 deposition of drug molecules 
 or active pharmaceutical ingredients ( apis ) , as well as aid substances , 
 allows to achieve new application routes like buccal or transdermal , in vivo drug targeting , acidic resistant coatings , and many more . for instance , spray 
 drying or electrospinning are shown to achieve pharmaceutically relevant 
 molecular coatings . surprisingly , the deposition via physical vapor 
 deposition or drop casting is hardly recognized even though such processes 
 are fast and reproducible , allowing the preparation of defined api 
 layers on solid surfaces . deposited solid organic layers can 
 be manipulated using temperature 
 treatments , which often result in changes in their polymorphic structures or morphologies . higher temperatures 
 mean that the unit cell thermally expands and that a system has more 
 energy present , allowing an adaption into different confinements . similarly , the usage of solvent annealing is a way to induce similar 
 changes compared to temperature treatments . in such an 
 experiment , the sample is in contact with a solvent vapor , resulting 
 in additional interactions being present . this additional 
 interaction induces alterations of the solid ; in the case of an amorphous 
 film , defined crystallization may be induced , and in crystalline films , 
 recrystallization is often observed , which 
 makes this technique a perfect choice for an identification of possible 
 morphologies and polymorphic structures . within this study the 
 preparation of thin layers of a model api 
 is investigated at a solid , flat silica substrate , providing the opportunity 
 to study interactions with various surface - sensitive methods like 
 atomic force microscope ( afm ) and x - ray diffraction . the model api 
 used is 5,5-diphenyl-2,4-imidazolidinedione ( phenytoin ) , which is 
 typically used due to its anticonvulsive , antiepileptic , and antiarrhythmic 
 properties within solid oral dosage forms ( i.e. , capsules and chewable 
 tablets ) or parenteral formulations . the api is chosen as it is known 
 to be isomorphic , that is , only one crystalline phase was observed . samples are prepared via vacuum deposition technique 
 revealing amorphous thin films at a silica surface . for the induction 
 of crystallization , the samples are exposed to various solvent vapors . the resulting films are investigated by afm and x - ray diffraction 
 experiments , and the resulting crystalline morphologies are explained 
 by solvent , the resulting films 
 are benchmarked versus dropcasted thin films and differences are elucidated . various solvents ( toluene , tetrahydrofuran , 
 2-propanol , ethanol , acetonitrile , and acetone ) were purchased from 
 various suppliers in spectroscopic grade . as substrates , conventional 
 glass slides ( roth , germany ) were cut in 2.5  2.5 cm pieces . prior to the experiments , the substrates were cleaned in 
 ethanol , acetone , and a 0.1 m naoh solution and were rinsed with isopropanol . vacuum 
 deposition of phenytoin was performed in a custom - made setup . 
 at a sublimation temperature of 115 c and a pressure 10 mbar , solvent annealing of the amorphous 
 films was performed by exposing 
 each phenytoin film to a different solvent vapor . a solvent vapor 
 atmosphere was achieved by putting an open glass vessel containing 
 the solvent next to the sample and a common enclosure . a direct contact 
 of the liquid solvents with the samples is prevented with this method . annealing times of 60 h at 25 c were used for all solvent annealing 
 steps . drop casting films were prepared by placing a 200 l 
 drop 
 containing the solute onto the glass slide . a petri dish covered the 
 sample to reduce the evaporation rates resulting in homogeneous film 
 formation over the entire glass slide . atomic force microscope 
 ( afm ) measurements were performed with 
 an easyscan 2 ( nanosurf , switzerland ) . all scans were performed in 
 noncontact mode using a tap  190 ( budgetsensors , romania ) 
 with a nominal resonance frequency of 190 khz . a scan rate of 0.5 
 s per line was used . specular x - ray diffraction experiments 
 were performed with a siemens 
 d500 in bragg  brentano configuration . the radiation was provided 
 by a copper sealed tube ( wavelength  = 0.154 nm ) and the beam 
 was guided through a slit system . the angular measurements 
 were recalculated into scattering vector notation via qz = 4 sin()/. theoretical 
 spectra were generated using mercury software package . the vacuum deposition of phenytoin onto a silica surface results 
 in an amorphous film . this amorphous film has a thickness of about 
 50 nm and is stable up to about 24 h after which crystalline structures 
 are present ( see figure 2 ) . the 
 morphology of phenytoin crystallites drastically changes as the samples 
 are exposed to a solvent atmosphere ( compare in figure 2 ) . after water vapor exposure a film consisting of similarly 
 small particles is observed but other than in the spontaneously crystallized 
 film a certain long - range order is present . this is typical for spherulitic 
 growth . using a tol vapor results in the formation of more plate - like 
 structures and some areas still exhibiting particle - like structures . 
 changing the solvent to thf results in the observed morphology of 
 phenytoin being larger elongated structures . in addition , the film 
 has areas where the substrate can be identified showing that thf vapor 
 assists in dewetting of the film from the surface ; thus , holes in 
 the film form during the solvent vapor annealing process . the sample 
 exposed to the ipa vapor exhibits various small separated particles 
 as well as some elongated structures . in the sample annealed in an 
 etoh vapor , bar - like shape structures are present with a width up 
 to 1.6 m , a length of 5.0 m and a height of 340 nm . inmecn and dmk , respectively , the phenytoin molecules assemble in 
 structures which have an even smaller contact area with the surface , 
 that is , the lateral extension is reduced compared to the other samples . in addition , the shape of the crystallites is more square - like compared 
 to those observed in etoh vapor . for the determination of the 
 crystalline structures of the films 
 specular x - ray diffraction scans were performed and the data is depicted 
 in figure 3 . within such a scan net planes 
 which are parallel to the surface are investigated giving information 
 on the net planes which are in contact with the silica surface . the 
 measurements on samples which were either spontaneously crystallized , 
 vapor annealed in water or thf annealed reveal one peak over the entire 
 scan range at 8.0 nm . a comparison of this peak 
 position with the only known crystal structure of phenytoin with its 
 orthorhombic packing in a = 0.62 nm , b = 1.36 nm , and c = 1.55 nm spanning unit cell reveals 
 that this peak results from the 002 reflection . this means that phenytoin 
 crystallizes preferentially with this net plane parallel to the surface . afm height 
 images of various phenytoin thin films after spontaneous 
 crystallization ( a ) and the exposure to water ( b ) , toluene ( c ) , tetrahydrofuran 
 ( d ) , 2-propanol ( e ) , ethanol ( f ) , acetonitrile ( g ) , and acetone ( h ) 
 solvent vapors ( scale bar = 5 m ) . various x - ray diffraction patterns of phenytoin thin films after 
 the exposure to solvent vapors . within all other samples , the 002 peak is less intense than 
 the 
 020 peak at 9.2 nm , which shows that phenytoin 
 vapor annealed in tol , ipa , etoh , or dmk assembles preferably in a 
 direction different to the previous samples ; the solvent annealing 
 process is able to alter the interaction with the substrate , which 
 results in a deviating assembling of the phenytoin molecules with 
 respect to the silica surface . some of the x - ray patterns show different 
 peaks with varying relative peak intensities . this means that the 
 phenytoin crystals have a preferred orientation , but the solvent annealing 
 is not able to induce a unique direction . only within dmk and ipa 
 a solely 020 is present , which suggests that the flat surface of the 
 plate - like crystallites consists of this net plane . within the tol 
 sample , two peaks at 8.9 and 17.8 nm this strongly 
 indicates that this is due to a second polymorph or a solvate having 
 formed during the vapor annealing process . the vapor annealing 
 process consists of film deposition and a subsequent 
 annealing process requiring a large experimental and time - consuming 
 effort . drop casting is a simple technique for which a drop is placed 
 on , typically , a solid surface , followed by solvent evaporation . the 
 formed morphologies within phenytoin films prepared from various solvents 
 are depicted in figure 4 . the low water solubility 
 of phenytoin prevented the usage of water within this method . the 
 afm height images of the samples are prepared from etoh , tol , and 
 ipa and reveal the formation of long needle - like structures . the needles 
 expand beyond the image , showing that needles longer than 100 m 
 have formed . the needle - like structure shows a more pronounced 
 tendency to form a two - dimensional network . these two - dimensional 
 morphologies are even more dominant for samples prepared from thf 
 or dmk , whereby plate - like structures form during the drop casting 
 process . the x - ray investigation on the drop casted films reveal a 
 preferential order of the 002 net plane being parallel to the surface . only the ipa sample shows a reduced probability for this alignment , 
 and the 011 is more dominant . within the thf and dmk annealed samples , 
 a peak at 8.9 surprisingly , this second polymorph 
 is absent in the sample prepared from the tol solution , which in the 
 vapor annealing experiment showed the formation of this additional 
 polymorph . ( a ) afm height images of phenytoin samples prepared via drop casting 
 from ethanol ( a ) , toluene ( b ) , 2-propanol ( c ) , acetonitrile ( d ) , tetrahydrofuran 
 ( e ) , and acetone ( f ) onto silica surface ( scale bar = 30 m , 
 except for c for which the scale bar = 10 m ) . ( b ) x - ray diffraction 
 patterns of phenytoin thin films prepared via drop casting from various 
 solutions . such amorphous films are stable up to 1 day after which the 
 entire film is converted to a crystalline form . while the amorphous 
 form is expected to be preferable in the dissolution behavior , the shelf - life is not sufficient for any relevant application purpose ; 
 recrystallization on storage may result in strongly changed physio - chemical 
 properties and therefore on the in vivo behavior . within the dropcasting 
 experiments , an amorphous phase could not be identified that suggests 
 that the solvent assisted in the rapid formation of phenytoin crystals ; 
 a solution means that diffusion processes are easily accessible . in 
 addition , the evaporation of the solvent takes about 1 min for the 
 fasted samples ( dmk solution ) and about 30 min for tol , in accordance 
 with their differences in vapor pressures ( see table 1 ) . these differences in crystal formation time aid in the 
 formation of different crystalline structures . the amorphous films transit on ambient storage spontaneously 
 into 
 its crystalline form after a day . the high number of particles 
 suggest that the formation of nuclei and their growth into crystals 
 is taking place simultaneously . this is further supported by the fact 
 that the size of these particles is very similar indicating again 
 a nearly identical crystal initiation . these structures are similar 
 to structures observed previously which however where obtained via 
 a spin - casting process . however , such 
 small particular films clearly showed a favorable dissolution behavior . by solvent annealing a process is meant where the solvent vapor 
 fills the entire glass vessel and that a certain amount of the solvent 
 is able to condensate / interact with the amorphous phenytoin film . 
 as a result , the crystal morphologies within the various films exposed 
 to the various vapors are distinct . for the understanding of the various 
 interactions of the solvent vapors with the phenytoin molecules or 
 the silica surface , the polar ( p ) , apolar ( d ) , and h - bonding ( h ) contribution have to 
 be taken into account ( note : the electrostatic interaction is of no 
 importance , as charges within the solute and solvents are not present ) . an estimate for the different contributions can be obtained by the 
 comparison of the hansen  solubility parameters . these values 
 are either tabulated or can be determined 
 by solubility testing or calculations and are summarized for the materials 
 used in this work in table 1 . therefore , the mean value of those solvents 
 in which phenytoin shows a good solubility are chosen for further 
 considerations . this 
 is also reflected in the affinity radius of two substances which isa large ra value 
 means a poor affinity and a bad solvent quality are likely present . 
 for water phenytoin , a value of about 30 is obtained ( see figure 5 ) , which is large in accordance with the low solubility 
 of phenytoin in water . in addition , the 
 affinity of the solvent for the substrate surface can be estimated . a ra value of about 27.5 indicates that 
 an equally poor interaction strength is present for water with the 
 substrate surface . from this follows that the nucleation of phenytoin 
 is weakly influenced by the presence of water vapor . however , the 
 spherulite - type structures suggest that crystallization within some 
 spots along the surface is taking place earlier , inducing crystallization 
 of adjacent fractions of phenytoin ; the poor solubility means that 
 when dissolution takes place , supersaturation is easily obtained by 
 solvent evaporation , which commonly takes place in such an experiment . dispersive ( d ) , 
 polar ( p ) , and h - bonding ( h ) hansen - solubility 
 parameters and vapor pressures ( pv ) are 
 listed . x - ray diffraction 
 experiments of the spontaneously grown and the 
 water - treated samples show a preferential growth , with the 001 net 
 plane being parallel to the substrate surface . by visualizing the 
 arrangement of the phenytoin molecules in the unit cell ( figure 6 ) with respect to the 001 net plane , it can be seen 
 that h - bonds from the terminal oxygen and van der waals interactions 
 of the phenyl rings are alternating in contact with the silica surface . such an arrangement seems to be reasonable by means of the silica 
 substrate , which has both polar and apolar contributions . from this follows that the interaction with the silica surface causes an alignment 
 of the molecules with this specific direction . phenytoin ra = 22 , 
 thus , tol preferentially interacts with the api molecules . as a result 
 of better solubility , the crystallites forming during the annealing 
 process are larger ; a higher saturation concentration means that crystallization 
 is slowed down , which typically results in the formation of less but 
 bigger crystallites . interestingly , the x - ray diffraction measurements 
 reveal a preferred orientation of the 010 , which is different to the 
 sample annealed in h2o or crystallized under ambient conditions 
 but with some fraction still crystallizing in a 002 orientation . the 
 inspection of the unit cell in terms of a 010 contact plane shows 
 that in this orientation only the phenyl rings are in contact with 
 the surface , which indicates that the silica this might be due to tol being able to penetrate the 
 amorphous phenytoin film and to assemble at the silica surface . this 
 provides new interactions and the formation of crystallites with a 
 010 orientation results . calculated solvent interaction radii for the 
 various solvents either 
 for phenytoin or the silica surface . the preparation of drop - casted films from a tol solution 
 results 
 in the formation of needle - like structures , while plate - like structures 
 are absent . a drop casting process means that the entire api is dissolved 
 and individual molecules are present in the solvent . as the vapor 
 pressure is relatively low for tol ( see table 1 ) , evaporation of the solvent is slow . this results in api molecules 
 having sufficient time to assemble into a low energetic crystal site 
 which for phenytoin is located at the front of the needle . in addition 
 to the change in the morphology compared to the vapor annealing process , 
 the x - ray diffraction experiments show that these needles have a preferable 
 010 texture , indicating that the phenytoin molecules have a preferable 
 interaction of the polar and h - bonding sites with the silica surface . the additional 011 peak in the pattern suggests that some crystals 
 grow on account of another interaction . this is further 
 supported by the fact that the crystals are lying across each other 
 ( see figure 4 ) . the vapor annealing process 
 with other solvents reveals the formation 
 of structures with a more or less strong tendency for dewetting . again this can be explained by the fact that the interactions of the solvent 
 with either the api or the substrate has changed . thf has a small ra value together with phenytoin in accordance 
 with a high solubility of the api in this solvent . in addition , the 
 interaction of the solvent molecules with the silica surface is more 
 favorable compared to water or tol . this enhances the ability for 
 dewetting and a different morphology is observed . in the same manner , ipa , etoh , and mecn are good solvents and have an increasing tendency 
 to interact with the surface . this results in even stronger dewetting 
 from the surface and morphologies with separated structure form . further , 
 a stronger dewetting means that more material is present for the formation 
 of crystal structures . it seems that within most of the dewetted structures , 
 which are typically drop - like , a single crystal forms . this results 
 in the crystal size being larger in etoh or mecn vapors compared to 
 the ipa vapor . within the dmk annealed sample , however , dmk exhibit still a good solvent quality 
 for the api , which together with the high vapor pressure means that 
 more solvent is present , favoring the dissolution of a higher mass 
 of phenytoin , which are able to crystallize into larger crystals . the corresponding x - ray diffraction pattern shows that the thf 
 sample has a preferred 001 orientation , while the others show a 010 
 orientation . this means that in thf the polar sites of phenytoin favor 
 a contact with the silica surface . within the other solvents a 010 
 orientation suggests that the silica phenytoin interaction 
 is weak , which suggests that the adsorbed solvents again provide an 
 apolar surface and an assembling with the phenyl rings in close vicinity 
 of the surface results . in etoh , an intermediate situation is present 
 as the 010 and the 001 orientation are even likely . the drop 
 casting of phenytoin from etoh , ipa , or tol solutions 
 results in needle - like structures being present after the solvent 
 evaporation . all of these solvents have relatively low vapor pressures , 
 which means that evaporation is slow , and like mentioned earlier , 
 growth takes place at the front of the crystal . however , as the vapor 
 pressure exceeds 92 torr , the morphology drastically changes . this is most probably a result 
 from the molecules being not able to diffuse to the low energetic 
 sites , which for the needle - type morphology are at the needle head 
 or tail . as the solvent evaporates fast the api molecules adapt at 
 crystal sites which are in close vicinity and a more two - dimensional 
 structure results . the x - ray diffraction experiments reveal 
 a preferentially 001 orientation 
 for all samples with some disorder along the 010 direction . this means 
 that , while the morphology is completely different for the various 
 samples , preferred alignment of the phenytoin oxygen with respect 
 to the surface exist , that is , the solvent has no effect on the molecule 
 alignment during the fast drop casting process . from this follows 
 that the structures that assemble on the evaporation do most likely 
 form in the supersaturated bulk solution where strong interactions 
 with the surface are absent . fall onto the surface . as all structures show a certain extension 
 in two lateral directions ( most likely along the crystal a and b direction ) , this  fallen the 
 view is along the a axis together with most prominent 
 net planes . the x - ray investigations 
 reveal the presence of a peak for some 
 samples that is not explainable by the unit cell shown above . however , 
 as the peak position and its higher order peak are close to the 020 
 and 040 peak of the known unit cell , it is likely that this peak is 
 a result from a polymorph that has an extended b axis 
 compared to the known one . as various samples show this peak , it is 
 unlikely that this peak results from a solvate , that is , a crystal 
 packing that contains solvent molecules . furthermore , this phase is 
 observed for the vapor annealed tol sample and is also present within 
 the drop cast thf and dmk samples . typically , the appearance of a 
 thermodynamic unstable polymorph is a result from fast solvent evaporation , 
 which causes molecules to assemble into a structure that is different 
 to the stable low energetic phase . anyway , the 
 measurement and repeated measurements after 2 weeks did not show any 
 deviating x - ray pattern , which shows that this polymorph is stable 
 at least for 2 weeks . often the substrate surface is able to stabilize 
 such a thermodynamic unfavorable structures ; the surface mediates 
 the arrangement on account of altered api  surface interactions . the preparation of the various morphologies for a single material 
 typically allows to tune the physical and chemical properties . while 
 not tested , it can be expected that the dissolution properties , which 
 are of great interest for pharmaceutical application , are altered , 
 as shown elsewhere for similar films . the 
 usage of a vacuum deposition technique allows depositing the material 
 on any substrate providing the ability , for instance , to prepare patches 
 containing a biodegradable substrate ; such a process is often limited 
 by a solvent process as it dissolves the substrate material . introducing 
 a proper solvent for a subsequent solvent annealing process , which 
 does not affect the substrate surface , may assist in the formation 
 of a desired morphology with defined properties . the hsp parameters 
 of the substrate can be used to estimate the expected behavior , reducing 
 the experimental effort to find a proper material combination . vacuum deposition of phenytoin results in completely amorphous 
 thin films and different crystal morphologies with varying preferential 
 orientation with respect to the silica substrate can be induced via 
 solvent vapor annealing . the relatively slow vapor annealing process 
 results in a preferential crystal growth in the 010 direction on vapor 
 annealing in most of the tested solvents , while water and thf vapor 
 induce a preferential orientation in the 001 direction . in the case 
 of etoh , contrarily , 
 drop casting of phenytoin from different solvents results in distinct 
 morphologies , while the x - ray diffraction experiments reveal , in general , 
 a preferentially 001 orientation for all samples with some disorder 
 along the 010 direction . this suggests that preferred alignment of 
 the phenytoin oxygen with respect to the surface are present and suggests 
 that the solvent has no or little influence on the molecule alignment 
 during the fast drop casting process . the observed morphologies can 
 be explained using the concept of the hansen - solubility parameters , 
 considering further the vapor pressure of the solvents in use . the 
 x - ray investigations reveal the presence of peaks within the pattern 
 of some samples ( sa tol , dc dmk , thf ) , which are not explainable by 
 the known unit cell . the results indicate that these peaks are a result 
 from a polymorph that has an extended b axis . the 
 presence of this most likely thermodynamic instable polymorph does 
 not change even after 2 weeks , indicating the stabilization of this 
 elusive crystal structure via the solid substrate . the finding of 
 this study motivates the usage of a similar approach for many other 
 organic molecules within pharmaceutical or other research areas for 
 which the search for new morphologies and polymorphs is highly desired .
the controlled preparation of different 
 crystal morphologies with 
 varying preferential orientation with respect to the substrate is 
 of crucial importance in many fields of applications . in this work 
 , 
 the controlled preparation of different phenytoin morphologies and 
 the dependency of the preferential orientation of those crystallites 
 is related with the preparation method ( solvent annealing vs drop 
 casting ) , as well as the physical  chemical interaction with 
 the solvents in use . while solvent annealing induces the formation 
 of particular structures that are partially dewetted , the drop casting 
 technique from various solvent results in the formation of needle - like 
 and elongated structures , with each having a distinct morphology . 
 the morphologies are explained via the hansen solubility parameters 
 and correlated with the solvent vapor pressures . 
 x - ray diffraction 
 experiments reveal preferential orientations with respect to the solid 
 substrate and indicate the surface - mediated stabilization of an unknown 
 polymorph of phenytoin with an elongated unit cell in the b - axis .