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1 POLYMORFI 2005 ISSN: (pdf)

2 Fysikaalisen farmasian XVI vuosittainen symposium: NIUKKALIUKOISET LÄÄKEAINEET Tuohilampi OHJELMA 9.30 Tero Närvänen symposiumin avaus 9.40 Martti Ovaska Niukkaliukoisuus tutkimuksen perspektiivistä Amie Kaukonen Niukkaliukoisten lääkeaineiden formulointi Vesa-Pekka Lehto & Mikko Koivisto Amorfisuuden määritysmenetelmät posteriesittelyt lounas Sabir Mirza Modification of erythromycin by solid dispersions and crystal engineering Tarja Toropainen Syklodekstriiniapuaineen käyttö inhaloitavissa lääkevalmisteissa kahvi Juha Juntunen Aihiolääkkeet kannabioidien liukoisuuden parantajina Hannele Eerikäinen Lääkenanohiukkaset: sovelluksia ja valmistusmenetelmiä symposiumin päätös FYSIKAALISEN FARMASIAN YHDISTYKSEN VUOSIKOKOUS vaihtoehtoisesti vapaata keskustelua, virvokkeita ja kotavisiitti halukkaille illallinen

3 POLYMORFI 2005 FYSIKAALISEN FARMASIAN YHDISTYKSEN JÄSENLEHTI XVI symposiumin ohjelma Sisällys Päätoimittajalta Esitysabstraktit Solubility in drug discovery Formulation of poorly soluble compounds Quantification of amorphous solids Modification of erythromycin by solid dispersions and crystal engineering Cyclodextrins in pulmonary drug delivery Water soluble prodrugs of cannabinoids Nanoparticles: applications and methods of manufacture Posteriabstraktit Characterization of potential non-erosive oral drug delivery systems: mesoporous MCM-41 and silicon powders Correlation between texture and tabletting properties of some pharmaceutical tablets.. 28 Development of new spraying system for microscale fluid bed granulator using electrostatic tomization Effect of electron withdrawing substituents on the acidity of p-vinylphenols through a vinylic double bond a comparison of calculated and experimental pk values a Hydrate screening application of cluster analysis to Raman spectra of nitrofurantoin crystals Mesoporous silicon microparticles enhanced solubility of poorly soluble drugs Oral controlled release of saccharides Raman spectroscopy for quantification of amphetamine in seized samples Ultrasound studies for starch acetate tablets Use of thermoanalytical methods in quantification of drug load in mesoporous silicon microparticles Osallistujat Päätoimittaja: Mikko Koivisto, Turun yliopisto mikjuko@utu.fi Julkaisija: Fysikaalisen farmasian yhdistys ry

4 POLYMORFI 2005 FYSIKAALISEN FARMASIAN YHDISTYKSEN JÄSENLEHTI Gradutiivistelmät Aseptisen valmistusmenetelmän validointi β-sitosterolin faasitransitioiden kinetiikan röntgendiffraktometrinen ja kalorimetrinen tutkimus Beta-sitosterolin kiteytyminen eri liuottimista Caco-2 solulinjan karakterisointi FDA:n malliyhdisteillä Ennustavat ja korreloivat laskennalliset menetelmät lääkevalmistekehityksessä: keinotekoiset neuroverkot, monimuuttuja-analyysit ja asiantuntijajärjestelmät In vitro -ihopermeaatiotutkimuksissa käytettävät mallimembraanit Isotermisen mikrokalorimetrin liukenemislaitteiston validointi ja mittauksia Jauheinhalaatiot ja niiden farmaseuttinen kehitys Karbamatsepiinin polymorfiasta Lääkevalmisteissa käytettävien biohajoavien polymeerien turvallisuuden tutkiminen.. 48 Nanopartikkelit lääkeaineiden kohdentajina N-heksaanin, 1-hekseenin, 1-heksyynin, 1-dekeenin ja undekyleenihapon soveltuvuus lääkeaineella ladatun huokoisen piin termiseen hydrosilylaatioon Nopeasti hajoavan tablettivalmisteen kehittäminen kahdelle suuriannoksiselle lääkeaineelle 51 Tablet disintegration: Effect of temperature and ph of aqueous disintegrating fluid and influence of properties of diluent on the behaviour of superdisintegrants The effect of different granulators on the properties of granules and tablets Uusien lääkeainemolekyylien imeytymisen arviointi ja oligopeptiditransportteri PepT1. 54 Virusten ja DNA-plasmidien annostelu nano- ja mikropartikkelien avulla Lisensiaatintutkimustiivistelmät Melting behaviour and quantification of low amorphous levels in sugars and sugar alcohols 57 Tablettien tekstuuritutkimus - uusia suuntauksia farmaseuttiseen fysiikkaan Väitöskirjatiivistelmät Increasing process understanding of wet granulation by spectroscopic methods and dimension reduction tools Role of exogenous and cell curface glycosaminoglycans in non-viral gene delivery Starch acetate as a coating polymer for oral extended release products film-forming ability, permeability and plasticization Starch-acetate films and microparticles degradation, erosion and drug release in vitro. 66 Artikkeli PAT ja fysikaalinen farmasia Fysikaalisen farmasian yhdistyksen tukijat Päätoimittaja: Mikko Koivisto mikjuko@utu.fi Julkaisija: Fysikaalisen farmasian yhdistys ry

5 PÄÄTOIMITTAJALTA Hyvät yhdistyksen jäsenet ja XVI symposiumin osallistujat Kädessäsi (tai ruudullasi) on erikoispaksu Fysikaalisen farmasian yhdistyksen jäsenlehti Polymorfi. Luettavanasi on seitsemänkymmentä sivua tiukkaa asiaa fysikaalisen farmasian eri osa-alueilta. Tämän Polymorfin paksuus johtuu siitä, että tästä numerosta päätettiin tehdä myös Fysikaalisen farmasian XVI vuosittaisen symposiumin abstraktikirja. Tavanomaisten gradu-, lisensiaatintutkimusja väitöskirjatiivistelmien lisäksi luettavanasi on myös symposiumissa kuultavien ja nähtävien esitysten ja posterien abstraktit. Onpa mukana myös yksi artikkelikin. Tämä Polymorfi tullaan symposiumin jälkeen julkaisemaan elektronisessa muodossa Fysikaalisen farmasian yhdistyksen kotisivuilla osoitteessa Elektronin versio on värillinen, ja lehdessä olevat verkko- ja sähköpostilinkit toimivat lisäksi sisällysluettelon otsikoita klikkaamalla pääsee suoraan ao. tiivistelmään. Tämänkertaisessa numerossa ei ole salasanasuojausta, vaan se on vapaasti kaikkien luettavissa. Siitä huolimatta muistakaa maksaa jäsenmaksunne. Yhdistyksen kotisivuja kannattaa muutenkin seurata aina välillä. Fysikaalisen farmasian symposium kokoaa vuosittain yhteen alan kotimaiset huippuosaajat. Symposiumin tieteellinen ohjelma koostuu eripituisista suullisista esityksistä sekä posterisessiosta. Ohjelman löydät tämän lehden toiselta sivulta. Muistakaa, että tieteellisen ohjelman lisäksi symposiumin epävirallisissa osuuksissa on loistavat mahdollisuudet keskusteluun sekä uusien kontaktien ja yhteistyökuvioiden luontiin. Vapaamuotoinen keskustelu ja rentoutuminenkaan ei missään nimessä ole kiellettyä. Tänä vuonna symposium järjestetään Orion Pharman tarjoamissa tiloissa Vihdin Tuohilammella. Tästä johtuen perinteinen illallisbuffet on vaihtunut ihan oikeaksi illalliseksi. Mutta ei hätää: virvokkeet eivät lopu tänäkään vuonna. Hyvää sympparia ja antoisia sekä opettavaisia lukuhetkiä! Turussa Mikko Koivisto 5

6 ESITYSABSTRAKTIT 6

7 SOLUBILITY IN DRUG DISCOVERY Martti Ovaska Orion Pharma, P.O. Box 65, FI Espoo, Finland Solubility is one of the basic properties of compounds which deserve careful attention during the discovery process of new drug candidates. The thermodynamic solubility of a solid compound is the amount of the compound in a saturated aqueous solution in equilibrium with the most stable crystal form of the material. It is represented usually as log(s), where S is the concentration in mol/l. It is important to make a difference between solubility and rate of dissolution. For a solid, the thermodynamic solubility reflects the true solubility of the most stable crystal form; therefore, the solubility is not affected by the crystal form. Different crystal forms may have considerably different dissolution rates. Experimental solubility may depend strongly on ph, temperature and the purity of the sample. The equation (1) of Meylan and Howard [1] correlates the solubility with the octanol/water partition coefficient log(p o/w ) and the molecular weight MW of the compound. The term Σf i is a sum of structure dependent correction factors. log(s) = log(p o/w ) MW + Σf i (1) Equation (1) shows that both increasing the lipophilicity log(p o/w ) of a compound by one unit and increasing the molecular weight by 100 decreases solubility by about 0.8 log unit. Analysis of marketed oral drugs and oral drugs in different clinical development phases (data up to January 2000) gave two main results [2]. Firstly, the mean molecular weight of orally administered drugs in development decreases gradually on passing through each of the different clinical phases (MW(PI) > MW(PII) > MW(PIII) > MW(marketed drugs)). Secondly, the compounds discontinued from a particular phase have higher log(p) than compounds progressed into the next phase of development. It has been also estimated that the average molecular weight and lipophilicity of the screening compounds in drug discovery phase have increased. The commonly used new technologies such as parallel and combinatorial chemistry and extensive use of commercial screening compound libraries in the discovery phase have contributed to this trend. Typical solubility range of marketed oral drugs in log units is between -1 and -5 (from 30 mg/ml to 3 µg/ml when molecular weight is 300). The solubility, permeability and potency are interrelated. Figure 1 depicts graphically a rule of thumb for the minimum acceptable solubility as a function of clinical potency (projected dose) and intestinal permeability [3]. Figure 1. Minimum acceptable solubility (in µg/ml). The bars show the minimum solubility for low, medium, and high permeability (Ka) at a clinical dose. The middle three bars are for a 1 mg/kg dose. With medium permeability, a solubility of 52 µg/ml is required (from reference [3]). 7

8 During the drug discovery process the properties of the compounds under development, such as solubility, absorption, metabolism, potency and safety, must be optimised simultaneously. As these properties are mainly independent of each other the task is to find the common structural space where each of the properties is optimal. This is shown schematically in Figure 2. Figure 2. The optimal properties cover different areas of the structural space. During compound optimisation the overlapping area, as denoted here by a star, is search for. Computational models are used to predict the general drug-likeness of compounds. Typical models include Lipinski rule-of-five, solubility models, membrane permeability models, blood-brain barrier penetration models, metabolic stability models (e.g. CYP s and glucuronidation) and safety models (e.g. HERG and potentially toxic fragments). There is a number of solubility models reported in the literature. The most commonly used commercially available solubility prediction software include QikProp (Schrödinger), ACD/Solubility (ACD/Labs) and DS Accord for Excel ADME add-on (Accelrys Ltd.). One can expect an average accuracy of about one log unit with any of these models. In early discovery phases computational models are used in the design of the first screening libraries which may be purchased or synthesised in-house. In the hit-to-lead optimisation process models are used in parallel with experimental studies in the simultaneous optimisation of both the druglikeness and potency. A good lead is amenable to easy formulation and has good chances to survive through the later preclinical and clinical phases of development. REFERENCES [1] W.M. Meylan and P.H. Howard, Perspect. Drug Discov. Des. 19 (2000) [2] M.C. Wenlock, R.P. Austin, P. Barton, A.M. Davis, and P.D. Leeson, J. Med. Chem. 46 (2003) [3] C. Lipinski, Aqueous Solubility in Discovery, Chemistry, and Assay Changes. In Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability. Ed. H. van de Waterbeemd, H. Lennemas, and P. Artursson. Wiley-VCH, Weinheim, Germany, 2003, p

9 FORMULATION OF POORLY SOLUBLE COMPOUNDS Ann Marie (Amie) Kaukonen Viikki Drug Discovery Technology Center, Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki Due to the present hit-to-lead selection process the formulator is likely to meet increasing numbers of candidate drugs with poor aqueous solubility hence running the risk of poor oral bioavailability. Classically compounds have been regarded poorly soluble when their aqueous solubility has been less than 100 µg/ml. There is, however, not one particular limiting solubility, but the potential for solubility (or dissolution) to present itself as the limiting step for oral absorption is determined by the triad of dose (i.e. potency and metabolic stability), solubility and permeability [1,2]. This concept is evident also in the Biopharmaceutical Classification System (BCS) where oral absorption potential is classified according to the permeability and the dose-based solubility of a compound [3]. Compounds classified according to the BCS as belonging to class II (high permeability, low solubility) are likely to exhibit solubility or dissolution rate limited absorption, since the amount permeating will be limited by the amount (concentration) of compound available. However, the BCS is based on solubility in aqueous buffers, which for lipophilic compounds may gravely underestimate their solubility in small intestinal fluids containing bile salts and phospholipids [4,5]. This should be kept in mind especially with highly lipophilic compounds, which derive relatively higher benefits from solubilisation into the mixed micelles (higher solubilisation ratio) [6]. Among the reasons for poor aqueous solubility of a molecule are low polarity/high hydrophobicity, high lipophilicity and/or high crystal energy [2]. The reason/s for poor solubility will impact on the feasibility of a particular formulation strategy as will the dose that needs to be incorporated into the formulation. Awareness of the dissolution process as presented in the modified Noyes-Whitney equation will provide insights to the means available for improving the dissolution rate of poorly soluble compounds [7]. J = dm dt = D A (C h s C b ) = K A (C s C b ) J = amount of material dissolved and transported across stagnant diffusion layer per unit time D = diffusion coefficient (diffusivity) h = thickness of stagnant/unstirred diffusion layer A = surface area of dissolving solid K = dissolution rate constant C s = concentration in saturated diffusion layer C b = concentration in bulk solution Based on the above, the two main approaches for improving dissolution are to increase the surface area by reduction of particle size and to improve the (apparent/local) solubility of the compound. The implementation of a particular approach may involve physical, mechanical, chemical and/or formulation (excipient) based strategies as illustrated in the following table (Table 1) [7-16]. 9

10 Table 1. Strategies to improve the oral absorption of compounds having solubility or dissolution limited absorption Approach Chemical Physical Formulation Excipient Particle size - Micronisation - Engineering Crystal habit Increase A Wetting Soluble excipients & Wetting agents - sugars - co-solvents - surfactants - polymers Salt form Pro-drug Buffering agents Increase C s Physical state - Amorphous - Polymorph - Pseudopolymorph/solvate Solubilisation - Micellar - Co-solvent - Complexing Surfactants Co-solvents Polymers Cyclodextrins Increase A & Increase C s Solutions, microparticulate and/or amorphous state Solutions or dispersions in carriers Co-solvents Polymers Lipids Emulsifying Mixtures of above Complexation Cyclodextrins (Calixarenes) REFERENCES [1] C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 23: 3-25 (1997) [2] C. A. Lipinski. Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacological and Toxicological Methods 44: (2000) [3] G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. Theoretical basis for a biopharmaceutic drug classification: correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical Research 12: (1995) [4] D. Hörter and J. B. Dressman. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv. Drug Delivery Rev. 25: 3-14 (1997) 10

11 [5] W. N. Charman, C. J. H. Porter, S. Mithani, and J. B. Dressman. Physicochemical and physiological mechanisms for the effects of food on drug absorption: The role of lipids and ph. J. Pharm. Sci. 86: (1997) [6] T. S. Wiedmann and L. Kamel. Examination of the solubilization of drugs by bile salt micelles. J Pharm Sci 91: (2002). [7] C. Leuner and J. Dressman. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 50: (2000) [8] B. C. Hancock and G. Zografi. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci 86: 1-12 (1997) [9] L. Yu. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Advanced Drug Delivery Reviews 48: (2001) [10] L.-F. Huang and W.-Q. T. Tong. Impact of solid state properties on developability assessment of drug candidates. Advanced Drug Delivery Reviews 56: (2004) [11] D. Singhal and W. Curatolo. Drug polymorphism and dosage form design: a practical perspective. Advanced Drug Delivery Reviews 56: (2004) [12] A. T. M. Serajuddin. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 88: (1999) [13] W. N. Charman. Lipids, lipophilic drugs, and oral drug delivery - some emerging concepts. J. Pharm. Sci 89: (2000) [14] C. W. Pouton. Lipid formulations for oral administration of drugs: non-emulsifying, selfemulsifying and self-microemulsifying drug delivery systems. Eur. J. Pharm. Sci. 11: S93- S98 (2000) [15] T. Loftsson and M. E. Brewster. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci 85: (1996) [16] V. M. Rao and V. J. Stella. When can cyclodextrins be considered for solubilization purposes? J Pharm Sci 92: (2003) 11

12 QUANTIFICATION OF AMORPHOUS SOLIDS Vesa-Pekka Lehto & Mikko Koivisto Laboratory of Industrial Physics, Department of Physics, University of Turku, FI Turku ABSTRACT Almost all the solid materials from metals to proteins can exist in amorphous forms. The amorphous material differs from its crystalline counterpart in that the atoms, ions or molecules comprising the solid material does not occupy space according to any three-dimensional systematic crystal structure but the long-range order between the atoms/ions/molecules is missing. The material is in a disordered state. The difference between the amorphous solid and the corresponding liquid is in the viscosity. As the mutual motions of atoms/ions/molecules is restricted in the amorphous solid its viscosity is higher. The overriding issues for pharmaceutical amorphous solids are the physico-chemical properties, stability and bioavailability. The importance of amorphous solids derives its origin from their useful properties (higher solubility, higher dissolution rate, better compression characteristics), common occurrence (can be produced deliberately or inadvertently e.g. during powder processing) and instability (physical and chemical) relative to corresponding crystals. Thus, it is normally of utmost importance to be able to quantify small degrees of amorphicity and hence ascertain the manufacturability and performance of the solid dosage form. The main topics discussed here involve the structural, thermodynamic and kinetic background of amorphous solids. The theoretical approach is elementary to understand the results obtained when utilized various techniques; the information from different sources is of different type and not on the same line. In the oral presentation it will be concentrated on the potential methods suitable to quantify amorphicity. AMORFISUUS Jäähdytettäessä lasia (aineen amorfinen muoto) muodostavaa materiaalia on jäädytysprosessi liian nopea, jotta kiteytyminen tapahtuisi. Tämä saattaa johtua siitä, että jäähdytys on äärimmäisen nopea (metallit) tai että molekyylien koosta ja muodosta johtuen kiteytymisprosessi ei ole suosiollinen (polymeerit, proteiinit). Tällöin jäähdytettäessä materiaali sulamispisteensä T m alapuolelle ei havaita entalpian eikä tilavuuden muutoksessa epäjatkuvuutta. Systeemi on muodostanut siis alijäähtyneen nesteen. Jäähdytettäessä alijäähtynyttä nestettä edelleen pyrkii systeemi normaalisti jollain alijäähtymisasteella kiteytymään joko stabiiliksi tai metastabiiliksi kiinteäksi aineeksi. Jossain tapauksissa (materiaalista riippuen) voi kuitenkin käydä niin, että kiteytyminen on kineettisesti estynyt. Tämä johtuu siitä, että molekyylien liikkuvuus (mobiliteetti) on tullut liian alhaiseksi johtuen viskositeetin kasvusta, jolloin aine ei voi molekyylien uudelleenjärjestymisten kautta kiteytyä eikä toisaalta myöskään omata alijäähtyneen nesteen rakennetta. Materiaali jää siis lasimaiseen tilaan, missä molekylaarinen rakenne on jähmettynyt. Transitiota kutsutaan lasisiirtymäksi ja sen lämpötilaa lasisiirtymälämpötilaksi T g. Lasisiirtymässä (muutos alijäähtynyneestä nesteestä lasitilaan lämpötilaa laskettaessa) molekyylien väliset sidokset eivät oleellisesti muutu, vaan molekyylien translaatioja rotaatioliike pienenevät dramaattisesti ja jäljelle jää pääosin vain molekyylinen värähdysliike. Lasisiirtymää voidaan täten karakterisoida lämpökapasiteetin C p askelmaisella muutoksella, joka puolestaan on entalpian H osittaisderivaatta lämpötilan T suhteen (C p = ( H/ T) p ). Havaitaan, että transitio riippuu molekyylien mobiliteetista eikä siihen liity lämmön vaihtumista; transitio ei ole termisesti aktiivinen. LASITRANSITIO Lasisiirtymää ja sen luonnetta voidaan tarkastella monen eri lähestymistavan avulla, eikä yksittäistä yleistä ilmiötä selittävää teoriaa ole vieläkään hyväksytty. Eräs tapa on tarkastella lasisiirtymää termodynaamisena toisen kertaluvun faasitransitiona, missä Gibbsin energian ensimmäiset osittaisderivaatat lämpötilan ja paineen suhteen ovat nollat, mutta toiset osittaisderivaatat poikkeavat nollasta 12

13 (transition yhteydessä ei tapahdu entalpian eikä tilavuuden muutosta). Koska kuitenkin T g on riippuvainen jäähdytysnopeudesta eikä lasitila ole termodynaaminen tasapainotila, ei lasisiirtymän kohdalla voida kuitenkaan puhua ideaalisesta toisen kertaluvun transitiosta. Toinen termodynaaminen lähestymistapa on tarkastella systeemin entropiaa S, joka tasapainotilassa on yhteydessä ominaislämpökapasiteettiin yhtälön C p = T ( S/ T) p kautta. Koska sekä lasitilassa (T < T g ) että kiteisessä tilassa olevan materiaalin lämpökapasiteetit aiheutuvat lähinnä molekyylien värähdysliikkeestä, ovat niiden C p :t likimain samat. Toisaalta taas alijäähtyneen nesteen (kumitilan, T > T g ) molekyylien liikkeellä on enemmän vapausasteita, ja C p -arvo on näin ollen korkeampi edellisiin verrattuna. Loogisena jatkumona seuraa, että nesteen C p -arvot ovat kaikkia kolmea jo mainittua arvoa suuremmat. Nyt voidaankin ajatella, että lasisiirtymä tapahtuu jollain tietyllä entropian ylimäärä -arvolla. Tästä voidaan päätellä, että T g :llä on olemassa jokin tietty (ainekohtainen) alaraja, vaikka jäähdytys tapahtuisi äärettömän nopeasti. Jos siis T g edustaa ylimäärä-entropian häviämistä, ei tämä arvo voi ylittää entropian muutosta, joka liittyy aineen transitioon nesteestä kiteiseksi. Muussa tapauksessa lasitilan entropia olisi pienempi kuin kiteisen tilan, ja tämä rikkoo termodynamiikan kolmatta pääsääntöä. Lasisiirtymälämpötilalle on siis olemassa alaraja T k (Kauzmannin lämpötila), ja käytännössä kokeellinen T g sijoittuu noin 20 K Kauzmannin lämpötilan yläpuolelle. Lasisiirtymää voidaan tarkastella myös (kineettisenä) molekylaarisena relaksaatio-prosessina nestettä jäädytettäessä. Relaksaatioaika τ riippuu lämpötilasta, siten että relaksaatioaika pitenee lämpötilan laskiessa. Vetysidoksia omaavan materiaalin kohdalla tämä relaksaatio liittyy lähinnä vetysidosten uudelleenjärjestäytymiseen. Jos materiaalin rakenteellinen relaksaatioaika τ r on lyhyt verrattuna havainnointiaikaan t o (kuten on tilanteessa T > T g ), on materiaali nesteenomaista, sillä näyte pystyy tällöin reagoimaan lämpötilanmuutoksiin jäähdytysprosessin aikaskaalassa. Tällöin näyte on tasapainossa jäähdytysohjelman kanssa. Jos taas relaksaatioaika on pitkä (T < T g ) ja t o < τ r materiaali käyttäytyy kuten kiinteässä olomuodossa, koska molekyyleillä on alhainen mobiliteetti, eivätkä ne pysty riittävän nopeasti seuraamaan lämpötilaohjelman aiheuttamia muutoksia. Lämpötilan muutoksen yhteydessä havaitaan lasisiirtymä, kun τ r t o. Ominaista amorfisille materiaaleille on myös tiettyjen lisäaineiden, liuottimista eteenkin veden, vaikutus lasisiirtymälämpötilaan. Vesi pyrkii kasvattamaan materiaalin vapaata tilavuutta ja lisäämään näin molekyylien mobiliteettia toimimalla plastisoijana. Tämä taas puolestaan vaikuttaa laskevasta T g -arvoon, mitä kuvaa alun perin lähinnä eri polymeeriseoksille johdettu Gordon-Taylor -yhtälö T g, mix w T 1 g,1 2 g,2 =. 1 + Kw T w + Kw 2 Yhtälössä w esittää alaindeksin ilmaiseman komponentin massaosuutta seoksessa, ja K esittää kyseisten komponenttien vapaiden tilavuuksien suhdetta. Vakio K voidaan laskea kaavasta (ρ 1 α 2 )/(ρ 2 α 1 ), missä ρ on tiheys ja α on lämpölaajenemiskertoimen muutos lasisiirtymäpisteessä (esim. laktoosi/vesi-systeemille K = 6,7). Toisaalta K voidaan arvioida myös kaavan (ρ 1 T g,1 )/(ρ 2 T g,2 ) avulla. Koska veden lasisiirtymälämpötilaksi on määritetty -135 C, on vedellä edellisen yhtälön mukaisesti lähes poikkeuksetta laskeva vaikutus materiaalien T g -arvoihin (esim. amorfiselle laktoosille T g = 97 C). Oleellista näissä tapauksissa on myös veden sorptiokäyttäytyminen, joka on luonteeltaan siis absorptiota. Täten veden sorptio amorfisiin materiaaleihin on verrannollinen näytteen massaan eikä pinta-alaan kuten adsorption tapauksessa. 13

14 VALMISTUS Sen lisäksi, että jotkut materiaalit (esim. polymeerit) luonnostaan esiintyvät amorfisina, voidaan normaalisti kiteisenä esiintyvä materiaali joko tahallisesti tai tahattomasti tuottaa kokonaan tai osittain amorfiseksi. Menetelmiä, joissa amorfista materiaalia syntyy, ovat mm.: - Liuoksesta nopeasti sakkauttaminen (ph:n muutos, siemenkiteet) - Sulan nopea jäähdytys (sammutus) - Partikkelikoon pienentäminen jauhatus / myllytys sumukuivaus kylmäkuivaus - Hydraattimuotojen dehydratoiminen. Vaikka amorfinen muoto onkin termodynaamisesti epästabiili, ja se pyrkii muuttumaan stabiiliksi kiteiseksi muodoksi kinetiikan riippuessa säilytysolosuhteista (kosteus/lämpötila), pyritään tietyissä tapauksissa materiaali nimenomaan saattamaan amorfiseen muotoon. Amorfinen ja vastaava kiteinen materiaali ovat kemiallisessa mielessä (molekyylitasolla) identtiset, joten niiden terapeuttinen vaikutuskin on identtinen. Kuitenkin kiderakenteella (tai sen puuttumisella) on suuri merkitys materiaalin fysikaaliskemiallisiin ominaisuuksiin vaikuttaen mm. materiaalin tiheyteen, optisiin ja mekaanisiin ominaisuuksiin, sähkönjohtavuuteen, viskositeettiin, kosteuden sorptiokäyttäytymiseen sekä fysikaaliseen ja kemialliseen stabiiliuteen. Farmaseuttisessa mielessä yksi merkittävimmistä eroista kiteisen ja amorfisen materiaalin välillä on vesiliukoisuus amorfisen aineen ollessa yleisesti huomattavasti liukoisempaa, tai ainakin nopeammin liukenevaa. Etenkin huonosti veteen liukenevien materiaalien kohdalla amorfisen materiaalin hyväksikäyttö saattaa mahdollistaa muuten soveltumattoman lääkeyhdisteen käytön, sillä esim. suun kautta nautittavien lääkkeiden on liuottava ruuansulatuskanavassa, ennen kuin ne voivat imeytyä systeemiseen verenkiertoon ja vaikuttaa terapeuttisesti. Tällöin kuitenkin amorfisen muodon on oltava riittävän stabiili, että valmistetta voidaan tuottaa, varastoida, jakaa ja käyttää ilman että siinä tapahtuu merkittäviä muutoksia. Tietyissä lääkevalmistuksessa käytettävissä prosesseissa (mm. jauhatus, puristus, mikronointi) saatetaan käsiteltävään materiaaliin tuottaa amorfisuutta tahattomasti, ikään kuin sivutuotteena. Tällöin amorfisuudella on tuotteen performanssin (toimivuuden) kannalta pelkästään negatiivinen vaikutus, ja tästä syystä sitä pyritäänkin useimmiten välttämään. Tuotettu amorfisuusmäärä saattaa kuitenkin olla liian pieni havaittavaksi erilaisilla analysointimenetelmillä mutta kuitenkin tarpeeksi suuri aiheuttamaan muutoksia tuotteen performanssiin. Esimerkkinä voidaan tarkastella 325 Meshin seulalla seulottua laktoosi-jauhetta, jonka partikkelien halkaisija on n. 100 µm. Arvioidaan laktoosimolekyylien halkaisijaksi 1 nm, ja oletetaan partikkelin pinnalle muodostuneen amorfinen kerros, jonka paksuus on kymmenen laktoosimolekyyliä. Kerroksen paksuus on niin pieni, että sen havaitseminen teoriassakin on vaikeaa esim. röntgendiffraktion (XRD) avulla (Scherrerin yhtälön mukaan CuKα-säteilyllä heijastusten puoliarvoleveydet ovat tällöin 1, kun 2θ = 20 ). Kerroksen paksuus on kuitenkin niin suuri, että se määrää partikkelin vuorovaikutuksen ympäristönsä kanssa. Kaavasta 1-((50-0,01)/50) 3 laskemalla saadaan amorfisen materiaalin osuudeksi 0,06%. Tämä osuus on niin pieni, että sen havaitsemin analyysimenetelmästä riippumatta on käytännössä mahdotonta. 14

15 MENETELMÄT Amorfisen materiaalin detektointiin ja sen kvantitatiiviseen määritykseen käytettäviä menetelmiä, joista tärkeimpiin ja yleisimmin käytettyihin perehdytään esimerkkien valossa suullisessa esityksessä, ovat mm.: - Röntgendiffraktio (XRD) - Kalorimetriset/termoanalyyttiset menetelmät Differentiaalinen pyyhkäisykalorimetria (DSC) Lämpötilamoduloitu DSC (MTDSC, MDSC) Isoterminen mikrokalorimetria (IMC) Liuoskalorimetria Termomekaaninen analyysi (TMA) Dynaaminen termomekaaninen analyysi (DTMA, DMA) Dynaaminen elektrinen analyysi (DEA) - Spektroskopiset menetelmät NIR Raman NMR - Kosteuden sorption määrittäminen gravimetrisesti - Muita Käänteinen kaasugromatografia (IGC) Termo-optinen mikroskopia (TOA) Tiheyden määrittäminen. 15

16 MODIFICATION OF ERYTHROMYCIN BY SOLID DISPERSIONS AND CRYSTAL ENGINEERING Sabiruddin Mirza a, Inna Miroshnyk a, Jyrki Heinämäki a, Jukka Rantanen a,b, Leena Christiansen a & Jouko Yliruusi a,b a Pharmaceutical Technology Division, University of Helsinki b Viikki Drug Discovery Technology Centre (DDTC), University of Helsinki, Finland Poorly water-soluble compounds with dissolution rate-limited low oral bioavailability present one of the major challenges in pharmaceutical development. There are several techniques [1-3] to increase the aqueous solubility of such compounds, including: particle size reduction modification of the crystalline form formulation of the drug as a solid dispersion. For many compounds, however, decreasing the particle size may not lead to a significant or adequate enhance in bioavailability. Moreover, the common way to reduce the particle size by milling may result in the particles with a broad size distribution, decreased crystallinity, poor flow properties, and static charges. The crystal form modification is not always feasible due to stability issues. An advantage of the solid dispersion technique is that it allows several mechanisms of solubillization such as micronization, improved wettability, dissolution of the drug in the hydrophilic carrier, absence of aggregation, and conversion of the drug to the amorphous state to be simultaneously employed. [4] In this presentation, two different approaches to modify solid-state properties of a model drug, erythromycin dihydrate (ED), are discussed. The first part deals with a development of solid dispersion of the drug in a water-soluble polymer, polyethylene glycol 6000 (PEG). The solid dispersions, when characterized by variable-temperature X-ray powder diffraction, revealed that ED was predominantly transformed to its anhydrous form during hot-melt processing. The temperature/composition phase diagram of the solid dispersions constructed by using hot-stage microscopy and differential scanning calorimetry suggested the formation of a monotectic. In summary the factors that may contribute into the dissolution rate improvement of the drug from the solid dispersion formulation are inferred. In the second part of the presentation, a particle engineering technique for in situ micronization of the model compound is introduced. A batch crystallizer (Figure 1) was used for the recrystallization of ED in the presence of adsorbed polymer, hydroxypropylmethylcellulose (HPMC), to control the crystal growth, and subsequently the final crystal size, shape and surface properties. Figure 1: A batch crystallizer used in the recrystallization experiments. 16

17 The nature of the HPMC-induced modifications of the drug particles was studied by means of various analytical techniques. Thus, the relationship between solid-state properties, crystal morphology and powder properties of the drug was deduced. Crystallization protocol for ED, which utilizes the HPMC as an additive in the crystallization media, is described. Finally, it is shown that by implementing the controlled crystallization technique micronized particles with narrow size distribution as well as improved handling properties and processability can be obtained. REFERENCES [1] Chiou W.L. and Riegelman S., Pharmaceutical applications of solid dispersion systems. J.Pharm.Sci. 60, [2] Serajuddin A. T. M., Solid dispersion of poorly water soluble drugs, early promises, subsequent problems and recent breakthrough. J. Pharm. Sci. 88, [3] Leuner C. and Dressman J., Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. & Biopharm.50, [4] Ford J.L., The current status of solid dispersions, Pharm. Acta Helv. 61,

18 CYCLODEXTRINS IN PULMONARY DRUG DELIVERY Tarja Toropainen a, Pekka Jarho a, Kristiina Järvinen b, Henna Vihola c, Jouni Hirvonen c & Tomi Järvinen a a Department of Pharmaceutical Chemistry, University of Kuopio, Finland b Department of Pharmaceutics, University of Kuopio, Finland c Division of Pharmaceutical Technology, University of Helsinki, Finland INTRODUCTION Cyclodextrins (CDs) are a group of cyclic oligosaccharides which has been used as excipients in pharmaceutical formulations. CDs have, for example, been used to increase the water solubility and dissolution rate of drugs in ophthalmic, intravenous and oral formulations [1]. Furthermore, they can also be used to improve drug stability and bioavailability, prevent drug:drug or drug:excipient interactions or reduce bad taste/odor of drugs. Figure 1: An example of a drug:cyclodextrin complex formation Recently, there has been an increased number of publications dealing with pulmonary applications of CDs. The systemic delivery of inhaled drugs requires various challenges to overcome. In addition to drug deposition and safety issues, there is also a need for rapid dissolution of inhaled particles since insoluble particles are removed via mucociliary clearance of uptake of alveolar macrophages [2]. This may lead to reduced absorption and bioavailability of a drug. We have shown earlier that the aerodynamic properties of a lipophilic drug (budesonide) in vitro are not impaired by complexation with γ-cd when the drug is delivered from a multiple-dose reservoirbased dry powder inhaler [3]. In the present study, we determined the dissolution behaviour of budesonide with γ-cd and evaluated the pulmonary safety of various CDs to be used in inhalation powders. METHODS Budesonide/γ-CD complex was prepared using a precipitation complexation method [3]. Dissolution profiles of micronised budesonide (420 µg), physical mixture (420 µg budesonide µg γ- CD) and budesonide/γ-cd complex (3000 µg; corresponding 420 µg budesonide) was determined in a shaking water bath (37 C, 100 rpm). A precisely weighed amount of budesonide, physical mixture or complex was dissolved in 20 ml of 1 % (m/v) γ-cd aqueous solution under sink conditions. Samples of 1 ml were taken at given intervals, replaced with an equal amount of the solvent and analyzed using HPLC. The pulmonary safety of various CDs (α-cd, β-cd, γ-cd, hydroxypropyl-β-cd and randomly methylated β-cd) was evaluated using Calu-3 pulmonary epithelial cells in vitro. Shortly, the cells were cultured onto 96-well plates hours prior to the experiment and incubated with various CD concentrations for 4 hours. The concentrations of β-cd were mm (due to its low water solubility) and the concentrations of other CDs were mm. The cell viability was determined by a MTT test [4] and the results were expressed as a viability ratio of treated cells vs. non-treated cells (%). 18

19 RESULTS The slowest dissolution was obtained for micronised budesonide. Figure 2 shows that after 30 minutes only 51 ± 12 % (mean ± SD) of plain budesonide was dissolved. The addition of γ-cd significantly increased the dissolution rate of budesonide. From physical mixture, 83 ± 7 % of budesonide was dissolved in 30 minutes. The dissolution was fastest and showed almost no variation between the trials from budesonide/γ-cd complex, from which 94 ± 2 % budesonide was dissolved in 30 minutes. Cumulative dissolved amount (%) (mean +/- SD) Complex Physical mixture Budesonide Time (min) Figure 2: Dissolution profiles of micronised budesonide (n=4), physical mixture of budesonide and γ-cyclodextrin (n=5) and budesonide/γ-cyclodextrin complex (n=3) (100 rpm, 37 C, in 1 % (m/v) γ-cd in water; mean ± SD). The results of the MTT test showed that the Calu-3 cell viability is strongly dependent on CD concentration (Figure 3). γ-cd and HP-β-CD decreased cell viability at concentrations of 100 mm and 50 mm, respectively. Therefore, they can be considered as the most tolerable CDs of this study. The most toxic CDs were β-cd and RM-β-CD which decreased cell viability at concentrations of 15 mm and 10 mm, respectively. 19

20 Cell viability (% of control) (mean +/- SD) α-cd γ-cd HP-β-CD RM-β-CD 0,05 0,1 0, CD concentration (mm) Cell viability (% of control) (mean +/- SD) ,01 0,05 0,1 0, β-cd concentration (mm) Figure 3: Calu-3 cell viability (%) after a 4-hour incubation with cyclodextrins (mean ± SD): α-cd (n=3-5), γ-cd (n=6), HP-β-CD (n=3) and RM-β-CD (n=3) (top) and β-cd (n=6) (bottom). Note the differences of scale on the x-axis. CONCLUSIONS The use of γ-cd significantly increased the dissolution rate of lipophilic model drug, budesonide. In addition, the dissolution profile of complexed budesonide showed almost no variation compared to plain budesonide and physical mixture. This indicates that the complexation of a lipophilic drug may be used to increase drug solubility and decrease the dissolution rate variability at the site of absorption. The toxicity study showed that CDs decreased cell viability only at high CD concentrations. Despite the lack of the local toxicity, the systemic safety needs also to be evaluated before a CD can be considered for pulmonary administration. As a conclusion, CDs remains to be potential pharmaceutical additives to be used in pulmonary drug delivery of lipophilic drugs. REFERENCES [1] Rajewski RA, Stella VJ: Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery. J Pharm Sci 85 (11): , 1996 [2] Labiris NR, Dolovich MB: Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 56: , 2003 [3] Kinnarinen T, Jarho P, Järvinen K, Järvinen T: Pulmonary deposition of a budesonide/γcyclodextrin complex in vitro. J Control Release 90: , 2003 [4] Hansen MB, Nielsen SE, Berg K: J Immunol Methods 119: ,

21 WATER-SOLUBLE PRODRUGS OF CANNABINOIDS Juha Juntunen a, Riku Niemi a, Jouko Vepsäläinen b, Krista Laine a & Tomi Järvinen a a Department of Pharmaceutical Chemistry, University of Kuopio, Finland b Department of Chemistry, University of Kuopio, Finland INTRODUCTION The active constituent of cannabis, 9 -tetrahydrocannabinol (THC), was isolated in The discovery of cannabinoid receptor in 1988 [1] led to search for endogenous compounds that bind to the cannabinoid receptor. Arachidonylethanolamide (AEA) [2] (Figure 1) was the first endogenous cannabinoid receptor agonist discovered. Later more endocannabinoids, like noladin ether (HU-310) [3] (Figure 1) were found. The potential use of cannabinoids in various neurological disorders like Alzheimer s disease, MS-disease and Parkinson s disease and control of pain, blood pressure and intraocular pressure (IOP) has recently been proposed. The pharmaceutical usefulness of cannabinoids is, however, limited by their lipophilic nature. Various approaches such as non-aqueous solvents, emulsifiers and cyclodextrins [4] have been used to overcome the poor aqueous solubility of both classical and endogenous cannabinoids. The poor aqueous solubility of cannabinoids can also be improved by incorporating ionizable or permanently charged pro-moiety to the cannabinoid structure. In this study we have synthesized different types of endocannabinoid (AEA and HU-310) prodrugs and evaluated their use as water-soluble prodrugs [5,6]. AEA O N H OH HU-310 O OH OH Figure 1. Endocannabinoids arachidonylethanolamide (AEA) and noladin ether (HU-310). MATERIALS AND METHODS Acidic (phosphate esters), basic (tertiary methyl piperazine derivatives) and permanent charge containing (quaternary methyl piperazine derivatives) prodrugs were synthesized (Figure 2). Various physicochemical properties (solubility, pk a, distribution coefficient) were determined for the synthesized molecules. Since prodrugs should release the parent compound after enzymatic (or chemical) hydrolysis in the body, the stability in several enzyme-containing media (serum, liver homogenate, cornea homogenate, pure enzyme) was studied. Also the in vitro cornea permeation and in vivo IOP reducing properties of phosphate ester prodrugs were evaluated and compared to results obtained by cyclodextrin formulation of the parent compounds. 21

22 Monophosphate ester: O R1= P OH R2= H OH O R1 O O R2 HU-310 Diphosphate ester: R1 and R2 = O P OH OH R= Tertiary prodrugs: N N O N N O P OH O OH N H AEA Phosphate ester: O R= R= N + N I O O R Quaternary prodrugs:: N + N + I I O N + N I O N + N + I I O Figure 2. Water-soluble AEA and HU-310 prodrugs. RESULTS Phosphate ester prodrugs increased the aqueous solubility of parent compounds considerably. The solubility of HU-310 phosphate at ph 7.4 was more than fold compared to HU-310. Phosphate ester prodrugs are almost completely in dianionic form at ph 7.4 and this ensures the good solubility. Basic prodrugs containing tertiary nitrogen atoms were not so soluble because they have pk a -values near the 7.4 and the molecules are not completely ionized. However, prodrug molecule with the pk a -value of 7.49 was surprisingly soluble at ph 7.4 and the solubility increases very rapidly near the pk a -value. This solubility behavior is not in agreement with the theoretical solubility but it can be explained by the ability of these molecules to form aggregates like micelles [7]. Micelles can incorporate the unionized, lipophilic form into the micelle interior. Solubilities of quaternary prodrugs were not dependent on the ph since there is a permanent positive charge in the molecule. Some of the quaternary compounds were quite unstable chemically and they were not very good substrates for the esterases present in serum and liver homogenate. However, one quaternary prodrug was an exception showing good aqueous solubility together with reasonable chemical stability and was quite rapidly cleaved in enzyme-containing media. The fact that these prodrug molecules contain negative (acidic) or positive (basic or permanently charged) charges may affect the absorption of these molecules. We tested how some of the synthesized phosphate ester prodrugs permeate rabbit cornea in vitro. The results were compared with the cyclodextrin formulation. The best permeation was achieved with the cyclodextrin formulations but also the prodrugs were effective. The prodrugs were cleaved just before or during the cornea permeation since only the parent compound was detected on the receiver side. Although there were differences in in vitro cornea permeation, the in vivo IOP reduction results are similar between phosphate ester prodrugs and cyclodextrin formulation of parent compounds. 22

23 CONCLUSIONS All the synthesized prodrugs were more soluble than the parent compounds AEA and HU-310. Although all of the quaternary prodrugs were very soluble and the solubility was not dependent on the ph, most of them were not very good substrates for esterases and some of them were chemically unstable. The solubility of tertiary amine prodrugs at ph 7.4 is highly dependent on the degree of ionization of these molecules and a slight change in ph can have dramatic effect on solubility. Phosphate esters showed good solubility and they released parent compounds after alkaline phosphatases in cornea and liver homogenate and in pure enzyme containing solution. Phosphate esters also work in vivo as the IOP studies show. REFERENCES [1] Devane, W. A.; Dysarz, F. A.; Johnson, M. R.; Melvin, L. S.; Howlett, A. C. Determination and Characterization of a Cannabinoid Receptor in Rat Brain. Molecular Pharmacology 1988, 34, [2] Devane, W. A.; Hanus, L.; Breuer, A.; Pertwee, R. G.; Stevenson, L. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992, 258, [3] Hanus, L.; Saleh, A.-L.; Fride, E.; Breuer, A.; Vogel, Z. et al. 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proceedings of the National Academy of Sciences U.S.A. 2001, 98, [4] Jarho, P.; Urtti, A.; Järvinen, K.; Pate, D. W.; Järvinen, T. Hydroxypropyl-beta-Cyclodextrin Increases Aqueous Solubility and Stability of Anandamide. Life Sciences 1996, 58, [5] Juntunen, J.; Huuskonen, J.; Laine, K.; Niemi, R.; Taipale, H. et al. Anandamide prodrugs. 1. Water-soluble phosphate esters of arachidonylethanolamide and R-methanandamide. Eur J Pharm Sci 2003, 19, [6] Juntunen, J.; Vepsäläinen, J.; Niemi, R.; Laine, K.; Järvinen, T. Synthesis, in vitro evaluation, and intraocular pressure effects of water-soluble prodrugs of endocannabinoid noladin ether. J Med Chem 2003, 46, [7] Roseman, T. J.; Yalkowsky, S. H. Physicochemical properties of prostaglandin F2 alpha (tromethamine salt): solubility behavior, surface properties, and ionization constants. J Pharm Sci 1973, 62,

24 NANOPARTICLES: APPLICATIONS AND METHODS OF MANUFACTURE Hannele Eerikäinen Orion Pharma PH.D. THESIS: Preparation of Nanoparticles Consisting of Methacrylic Polymers and Drugs by an Aerosol Flow Reactor Method (in review) Usually the diameter of nanoparticles used in pharmaceutical applications varies between ten and one thousand nanometers. The particles of this size, when consisting of the drug material only, are very unstable. Therefore, the nanoparticles need to be stabilised by a plastic material, polymer, suitable for a pharmaceutical application. The polymer gives the nanoparticles adequate mechanical hardness and rigidity. In addition, the polymer can be used to modify the properties of the nanoparticles, for example to control the solubility properties or to protect a fragile drug molecule. Nanoparticles can be classified according to their structure to two groups: matrix-type nanoparticles or capsule-type nanoparticles. In a matrix-type nanoparticle the drug is evenly distributed within the particle and the polymer and the drug form a solid, homogeneous particle. In a capsule-type nanoparticle, the polymer forms a hard shell, which encapsulates the drug. Several applications have been proposed for nanoparticles in the pharmaceutical field, such as increase in solubility and dissolution rate. Nanoparticles could also be used to target drug delivery into certain sites or organs within the body, for example into tumours. In addition, it has been proposed that nanoparticles could be used as carriers deliver DNA or proteins inside cells. The dissolution rate depends on the surface area of the dissolving particle according to Noyes- Whitney equation. One method to increase the surface area available for solvent is to decrease the particle size. dm/dt = the dissolution rate D = diffusion coefficient A = surface area available for solvent h = the thickness of the diffusion layer C s = saturation concentration C = concentration. dm DA = ( Cs C), dt h Several methods of manufacture of the nanoparticles have been shown in the literature. The most widely used methods include emulsion-based methods. In these methods the poorly water soluble drug and the polymer are dissolved in an organic solvent, for example in chloroform. Nanosized emulsion droplets of chloroform in water are formed and the resulting nanodroplets are hardened by evaporation the solvent. Usually, emulsion-based methods cannot be used for preparation of nanoparticles from water soluble drugs. Other similar methods are for example coacervation or precipitation, in which the polymer is precipitated using a poor solvent. Special milling methods, especially wet milling, can be used to grind larger drug particles to nanosized particles. In these methods the achievable particle size depends on the duration of treatment and the hardness of the material. Most currently used methods for the production of nanoparticles result in an aqueous suspension. Surface-active agents, surfactants, have to be added to make the suspension stable. If the nanoparticles could be prepared as dry powder, it would increase the stability of the particles. This research concentrated on manufacturing drug-containing polymer nanoparticles by an aerosol flow reactor method. In this method, first a solution containing the drug and the stabilising polymer was prepared. This solution was sprayed to form nanosized droplets having a diameter of approximately 300 nm, which were dried by evaporation of the solvent. The nanoparticles were then collected directly as dry powder. The particles prepared were matrix-type particles, and the drug and 24