(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`14 January 2010 (14.01.2010)
`
`PCT
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
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`(10) International Publication Number
`WO 2010/003811 Al
`
`(51) International Patent Classification:
`BOID 9100 (2006.0l)
`C07K 14137 (2006.0l)
`A61K 9116 (2006.0l)
`
`(21) International Application Number:
`PCT/EP2009/057760
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`23 June 2009 (23.06.2009)
`
`English
`
`English
`
`(30) Priority Data:
`08160212.0
`
`l l July 2008 (l l.07 .2008)
`
`EP
`
`(71) Applicant (for all designated States except US): BASF
`SE [DE/DE]; 67056 Ludwigshafen (DE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): HAFNER, Andreas
`[CH/CH]; Balkenweg 23, CH-4460 Gelterkinden (CH).
`BUTHE, Andreas [DE/DE]; Billungerstrasse 19, 48565
`Steinfurt (DE). VAN DER SCHAAF, Paul Adriaan
`[NL/FR]; I, rue des Muguets, F-68220 Hagenthal-le-Haut
`(FR). KAUFMANN, Franz [DE/DE]; Ferdinand-Weiss(cid:173)
`Strasse 57, 79106 Freiburg (DE). BRADLEY, Gordon
`[GB/CH]; Zirkelirain 27 A, CH-44 lO Liestal (CH).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT,
`TZ, VA, VG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, VG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR),
`OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML,
`MR, NE, SN, TD, TG).
`
`Published:
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`with international search report (Art. 21 (3))
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`(54) Title: AMPHIPHILIC PROTEINS AS MORPHOLOGY MODIFIERS
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`(57) Abstract: Disclosed is a process for modifying the morphology and/or polymorphism of an organic substance, which process
`comprises treating the solid substance, or a solution or dispersion thereof, with one or more amphiphilic proteins.
`MYLAN EXHIBIT 1012
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`

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`WO 2010/003811
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`PCT /EP2009/057760
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`- 1 -
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`Amphiphilic proteins as morphology modifiers
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`The present invention relates to a process for modifying the morphology and/or
`
`polymorphism of solid organic compounds, such as crystal size, habit and modification, with
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`amphiphilic proteins, a corresponding use of amphiphilic proteins and the modified solids
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`5
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`obtainable by the present process.
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`Solidification and especially crystallization is a key separation and purification unit in most of
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`the pharmaceutical, food and specialty chemical processes (for example pigments), with a
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`significant impact on the efficiency and profitability of the overall process. The majority of
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`10
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`pharmaceutical products contain active ingredients produced in crystalline form. Thus
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`crystallisation is of fundamental importance to the industry. For efficient downstream
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`operation (such as filtration, drying, compacting) and product effectiveness (e.g.
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`bioavailability, tablet stability) the control of crystal purity, size distribution and shape can be
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`critically important.
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`15
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`Typically pharmaceutical-grade crystalline products require a narrow particle size distribution,
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`which implies that the primary production process must be well-designed and tightly
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`controlled under optimal conditions. Control of crystal size and shape enables the
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`optimization of the dissolution rate and this may maximize the benefit while minimizing the
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`side effects. Many pharmaceuticals can form crystals that exhibit multiple morphological
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`20
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`forms and habits that are of critical importance to the formulation and end use properties of
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`the products.
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`Technical background
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`25
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`Figure 9 illustrates a typical crystallization process embracing the following steps:
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`(a) Organic molecules form randomly orientated molecular clusters by a diffusion process.
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`(b) These clusters can either break down to single molecules again or begin to form unstable
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`lattice formations called embryos.
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`(c) Such embryos can break down into clusters again or grow sufficiently to form stable
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`30
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`nuclei which precipitate out of solution (nucleation). Such critical size is dictated
`
`by the operating conditions (temperature, supersaturation, etc.).
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`(d) These nuclei then grow into larger crystallites which can continue to grow into single
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`crystals or come together to form aggregates of crystallites.
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`WO 2010/003811
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`PCT /EP2009/057760
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`- 2 -
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`(e) Such aggregates can range from soft aggregates that can be easily broken down to the
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`original crystallites to hard aggregates that can only be broken down by an aggressive
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`process such as milling.
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`5
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`Supersaturation is the driving force of the crystallization, hence the rate of nucleation and
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`growth is driven by the existing supersaturation in the solution. Supersaturation is defined as
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`concentration of the solute in excess of saturated concentration under given conditions of
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`temperature. Once supersaturation is lost, the solid-liquid system reaches equilibrium and
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`the crystallization process stops.
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`10
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`Nucleation and growth continue to occur simultaneously while the supersaturation exists.
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`Certain solvents, the presence of impurities or additives and compounds of similar chemical
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`type to the compound undergoing the crystallization process can strongly influence its
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`15
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`nucleation and crystal growth stages by changing the supersaturation properties of the
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`crystallization process.
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`Depending upon the conditions, either nucleation or growth may be predominant over the
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`other, and as a result, crystals with different sizes, different size distributions and habits
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`20
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`(shapes) are obtained.
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`Crystal habits can be, for example, cubic, tetragonal, orthorhombic, hexagonal, monoclinic,
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`triclinic, and trigonal.
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`25
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`Different polymorphs can also be produced by changes in the crystallization process.
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`Polymorphs are defined as crystalline phases that have different arrangements and/or
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`conformations of molecules in the crystal lattice. These crystal forms differ in packing,
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`thermodynamic, spectroscopic, kinetic, surface and mechanical properties.
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`30
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`Although polymorphs have the same elemental composition, polymorphs exhibit different
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`physico-chemical and physicotechnical properties such as free energy, entropy, heat
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`capacity, melting point, sublimation temperature, solubility, stability, dissolution rate,
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`bioavailability, hardness, compatibility, flowability, tensile strength and compressibility, etc.
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`WO 2010/003811
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`PCT /EP2009/057760
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`- 3 -
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`For this reason, polymorphism is of major importance in industrial manufacture of crystalline
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`products
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`The nature of a crystallization process is governed by both thermodynamic and kinetic
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`5
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`factors, which can make it highly variable and difficult to control. Factors such as impurity
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`level, mixing regime, vessel design, and cooling profile can have a major impact on the size,
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`number, and shape of crystals produced.
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`Poor control of crystal size and shape can also result in unacceptably long filtration or drying
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`10
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`times, or in extra processing steps, such as recrystallization or milling, and can influence the
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`purity of the product which is especially important in the food and pharmaceutical industries,
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`in which the crystals are consumed.
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`It is known that the morphology and size of bio-active substances can be affected by the
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`15
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`solvent used in the crystallization process. For example, monoclinic paracetamol is formed
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`by crystallization from ethanol, but the less stable polymorph, orthorhombic paracetamol, is
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`formed by slow crystallization from hot water only when multiple nucleation is prevented.
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`However, the choice of crystallization solvents is severely limited on toxicity grounds.
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`20
`
`A number of additives have already been used to influence either the growth or the
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`nucleation phase, resulting in modification of either the polymorphic form or the crystal habit.
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`In some cases, paracetamol serves here as a model substance.
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`Synthetic (co)polymers and surfactants have also been shown to modify the morphology of
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`25
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`bio-active substances but this has limited commercial value again on toxicity grounds.
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`W003/033462 proposes polymer libraries for initiating growth of crystal polymorphs and
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`describes the use of certain polymers to modify the crystallization of paracetamol: The
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`crystals are grown by cooling a solution of paracetamol in hot water. In the absence of
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`30
`
`polymers, these conditions would be expected to yield monoclinic paracetamol. There is a
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`significant bias toward the production of orthorhombic paracetamol when crystallizations are
`
`carried out in the presence of Nylons or halogenated polymers. Rodrfguez-Hornedo et al., 4._
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`Pharm Sci. (2004) 93(2), 449-60, describe the use of surfactants sodium lauryl sulfate and
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`sodium taurocholate
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`WO 2010/003811
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`PCT /EP2009/057760
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`- 4 -
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`on the crystallization of dihydrate carbamazepine.
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`Garekani et al., Int. J. of Pharmaceutics 208 (2000) 87, and literature cited therein, report
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`some methods for modifying the crystal habit of paracetamol by crystallization in the
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`5
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`presence of additives.
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`WO 05/115344 claims that a rapidly dissolving form of paracetamol is obtained after re(cid:173)
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`crystallization in the presence of a crystallization modifier, which may be a polymer, or a
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`protein such as albumin, papain, pepsin.
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`10
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`It has now been found that rapid nucleation of organic substances in solution may be
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`induced, even at elevated temperatures, by an amphiphatic protein, especially a
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`hydrophobin. It has also been found that such proteins alter the crystal growth behaviour of
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`the organic substance during the crystallization process yielding unexpected crystal habits
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`15
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`and crystal size distribution. Amphiphilic proteins like hydrophobins may be used as additives
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`during or after crystallization, e.g. in order to control the morphology (stabilization of meta(cid:173)
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`stable polymorphs) and the size distribution of organic compounds such as bio-active
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`substances, e.g. for cosmetical, biocidal, pharmaceutical or medical applications (such as
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`cosmetical actives, active pharmaceutical ingredients [APls], animal care products,
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`20
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`agrochemicals, biocides, pigments, dyestuffs) or to stabilize certain polymorphs. The
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`invention thus pertains to a process for modifying the morphology and/or polymorphism of an
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`organic substance, which process comprises treating the solid substance, or a solution or
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`dispersion thereof, with one or more amphiphilic proteins.
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`25
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`The process is advantageously carried out using a solution or dispersion of the organic
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`substance and/or solution or dispersion of the protein. The solution usually is one in a polar
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`solvent, often an aqueous solvent such as water, lower alcohol (such as methanol, ethanol,
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`propanol, isopropanol, butanol, isobutanol) or mixtures of water and lower alcohol, especially
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`water.
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`30
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`One of the most important aspects of this invention is the modification of crystal properties of
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`bio-active substances by employing the use of amphiphilic proteins during the crystallization
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`process.
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`PCT /EP2009/057760
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`- 5 -
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`Most bio-active substances are found to be poorly soluble in water, and it is known that
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`forming finer particles (micron and smaller) can improve their bio-availability or the
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`dissolution rate due to their increased surface area.
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`5
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`The present invention thus further pertains to a composition comprising an organic bio-active
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`substance and an amphiphilic protein, especially a hydrophobin, such as the compositions
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`obtainable in the process of the invention. The composition of the invention contains the
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`organic bio-active substance preferably in fine grain form, with mean particle sizes,
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`depending on the desired end use, e.g. ranging from 0.1 to 1000 micrometer, or in other
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`10
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`cases as detectable by dynamic light scattering ranging e.g. from 5 to 5000 nm, especially 20
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`to 2000 nm. Such particles may be free flowing, dispersed in a liquid, or especially
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`agglomerated or compacted. The amount of amphiphilic protein in the composition, e.g. in
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`the solid particle composition, may cover a wide range depending un the end use and
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`desired effect, ranging for example from about 0.0001 to about 10 %, often from 0.001 to
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`15
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`about 2 %, especially 0.01 to about 1 %, each by weight of the final composition.
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`Thus, one aspect of the present process relates to a modification which comprises a
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`reduction of the crystallite size.
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`20
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`Another aspect of the present process relates to a modification which comprises a change of
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`crystal habit.
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`A further aspect of the present process relates to a modification which comprises a change in
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`crystal morphology.
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`25
`
`30
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`The invention further relates to a modification of an organic solid which comprises a
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`combination of two or more of the following crystal properties:
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`(a) reduction of crystallite size; (b) a change of crystal habit and (c) a change in crystal
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`morphology.
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`Amphiphilic proteins possess both hydrophobic and hydrophilic properties and can be termed
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`as "nature's surfactants". A synonym to amphiphilic is "amphipathic".
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`WO 2010/003811
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`PCT /EP2009/057760
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`- 6 -
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`Amphiphatic proteins can physically adsorb on the surface of a solid substance to form a
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`surface possessing both hydrophobicity and hydrophilicity oriented in accordance with the
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`wettability of the surface being treated.
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`5
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`If the surface is hydrophobic, the hydrophobic side of the coating is in contact with the
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`hydrophobic surface being coated, and the outer surface of the coating is hydrophilic,
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`thereby increasing the water wettability of the surface being coated.
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`The surface active properties of proteins onto substrates can be assessed by interfacial
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`10
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`tension measurements, characterization of oil-in-water emulsions and contact angles with
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`water. The amphiphilic protein useful in the present invention is characterized by strongly
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`lowering the contact angle of water (WCA) on a hydrophobic surface (e.g. the surface of a
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`polyolefin or a Teflon® surface). Specifically, a 1 % b.w. aqueous solution or dispersion of the
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`amphiphilic protein useful in the present invention generallyshows a contact angle on a
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`15
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`polypropylen surface (specifically: PP homopolymer type HC115MO, Borealis, melt flow rate
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`= 4.0 g/10 min [230°C/2.16 kg]) which is lower than the contact angle observed for pure
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`water by 20 degrees or more, preferably 30 degrees or more, more preferably 40 degrees or
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`more, most preferably 45 degrees or more, and in some specific cases 50 degrees or more
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`(see Fig. 8; all WCA measurements according to static sessile drop method).
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`20
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`Hydrophobins, discovered in 1991, are a class of small secreted cysteine-rich amphiphilic
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`proteins present in fungi and fulfilling a broad spectrum of functions in fungal growth and
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`development. Hydrophobins are among the most surface active molecules and self(cid:173)
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`assemble at any hydrophilic-hydrophobic interface into an amphiphilic film (Biochimica et
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`25
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`Biophysica Acta - Reviews on Biomembranes - Volume 1469, Issue 2, 18 September 2000,
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`Pages 79-86).
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`Hydrophobins are typically readily soluble in water. Spontaneous self-assembly of
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`hydrophobins leads to the formation of an amphiphilic layer that remarkably reduces the
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`30
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`surface tension of water. A suggested mechanism of the function for hydrophobins can be
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`found in J. Biol. Chem., Vol. 282, Issue 39, 28733-28739, September 28, 2007:
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`Monomers multimerize to dimers, two of which form a tetramer. The tetramer may split into
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`two new dimers with hydrophobic surface areas aligned. These amphiphilic dimers precede
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`PCT /EP2009/057760
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`- 7 -
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`the formation of amphiphilic monolayer on hydrophobic-hydrophilic interface. At high
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`concentration, excess hydrophobin forms fibril structures.
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`Based on differences in hydropathy patterns and biophysical properties, hydrophobins are
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`5
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`divided into two categories: class I and class II.
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`Examples of Class I:
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`POH3 (PO) from Pleurotus ostreatus
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`TT1 (TT) from Talaromyces thermophilus
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`10
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`SC3 (SC) from Schizophyllum commune
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`Examples of Class II:
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`HFBI & HFBll (TR) from Trichoderma reesei
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`HCf-6 from Cladosporium fulvum
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`15
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`CU (Cerato-ulmin)
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`Purification and isolation of hydrophobins are described in the following references:
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`WO-A-96/41882 describes hydrophobins from edible fungi.
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`20 WO-A-00/58342 relates to purification of hydrophobin-containing fusion proteins by phase
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`extraction.
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`WO-A-01/57066 describes stabilization, solubilization and, related thereto, improved
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`application of hydrophobins due to sulfite treatment.
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`WO-A-01/57076 describes purification of hydrophobin via adsorption to Teflon beads and
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`25
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`elution by means of a detergent such as Tween at low temperatures.
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`United States Patent 7, 147,912 cites hydrophobins belong to the most surface-active
`molecules. With a maximal lowering of the water surface tension from 72 to 24 mJ m-2 at 50
`
`microgram/ml, SC3 (Schizophyllum commune) is regarded as the most surface-active protein
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`30
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`known. SC3 is a class 1 hydrophobin.
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`Further hydrophobins useful in the present invention, as well as sources and properties
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`thereof, are described inter alia in WO 96/41882 (see passage from page 1, line 14, to page
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`7, line 20, and examples 1 to 5); WO 03/10331 (see passage from page 1, line 4, to page 5,
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`line 20); or WO 06/103230 (see passage from page 3, paragraph 6, to page 12, 3rd line from
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`bottom of page); the specific passages mentioned are hereby incorporated by reference.
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`Surprisingly it has been found that amphiphilic proteins, especially hydrophobins, also affect
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`5
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`the morphological properties of organic substances and often give more advantageous
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`compositions than when solvents, polymers or synthetic surfactants are used.
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`The present process often is carried out by
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`10
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`i) combining the solution or dispersion of the protein in a polar solvent, and a solution or
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`dispersion of the organic substance in a polar solvent which is miscible with the solvent of
`
`the protein, or
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`ii) contacting the solution or dispersion of the organic substance in a polar solvent with a
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`15
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`surface impregnated with the protein.
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`One embodiment comprises:
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`(a) dissolving or dispersing the amphiphilic protein in a solvent;
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`20
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`(b) dissolving the organic substance in a solvent that is miscible with the solvent of the
`
`protein;
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`(c) mixing (a) and (b)
`(d) adjusting the physical environment of the mix to allow precipitation I crystallization of
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`the organic substance to occur in the presence of the amphiphilic protein.
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`25
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`A second embodiment comprises:
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`(a) dissolving or dispersing the amphiphilic protein in a solvent;
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`(b) adding (a) to a reaction vessel in which an organic substance is to be formed by a
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`30
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`chemical reaction;
`
`(c) allow the chemical reaction to occur in the presence of the amphiphilic protein;
`(d) adjust the physical environment of the mix to allow precipitation I crystallization of the
`
`organic substance to occur in the presence of the amphiphilic protein.
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`WO 2010/003811
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`PCT /EP2009/057760
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`- 9 -
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`A third embodiment comprises:
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`(a) dissolving or dispersing the amphiphilic protein in a solvent;
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`(b) dissolving the organic substance in a solvent that is miscible with the solvent of the
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`5
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`protein;
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`(c) mixing (a) and (b);
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`(d) wet milling the organic substance in the presence of the amphiphilic protein.
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`A fourth embodiment comprises:
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`10
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`15
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`the addition of "seeds" (stable nuclei) of the organic substance to the solution of the
`organic substance prior to or after the addition of the amphiphilic protein solution I dispersion.
`
`A fifth embodiment comprises:
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`Combination of the amphiphilic protein(s) with other additives, especially those that can
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`also influence the crystallization process of organic substances. Examples of such other
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`additives are salts (such as sodium chloride, ammonium salts) or further polymers
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`(especially soluble polymers including synthetic ones such as polyvinylpyrrolidone and
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`20
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`natural ones such as gelatine). Within this definition small quantities of solvents are
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`included.
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`Further, the invention includes the following embodiments, each of which may be combined
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`with each other:
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`25
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`• A process for modifying the morphology and/or polymorphism of an organic
`
`substance, which process comprises treating the solid substance, or a solution or
`
`dispersion thereof, with one or more amphiphilic proteins.
`
`• Said process wherein a 1 % b.w. aqueous solution or dispersion of the amphiphilic
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`30
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`protein(s) used is characterized by a contact angle on a polypropylene surface which
`
`is lower than the contact angle observable for pure water by 20 degrees or more.
`
`• Said process which comprises precipitation, crystallization or solid-solid phase
`
`transition of the organic substance.
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`• Said process which comprises combining the solution or dispersion of the protein in a
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`polar solvent, and a solution or dispersion of the organic substance in a polar solvent
`
`which is miscible with the solvent of the protein; or contacting the solution or
`
`dispersion of the organic substance in a polar solvent with a surface impregnated with
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`5
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`the protein.
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`• Said process which comprises wet milling the organic substance in the presence of
`
`the amphiphilic protein(s).
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`• Said process which comprises the addition of crystal seeds of the organic substance
`
`to the solution of the organic substance prior to, or after, the addition of the
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`10
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`amphiphilic protein(s).
`
`• Said process wherein a solution contains a further additive such as a salt and/or a
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`polymer.
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`• Said process wherein the organic substance is an organic compound, which is solid
`
`at 0° Celsius and soluble, partially soluble or dispersable in the polar solvent, for
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`15
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`example as a colloid.
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`• Said process wherein the organic substance is an organic compound from the
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`molecular weight range 80 to 1000, especially 100 to 500 g/mol, which is preferably
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`selected from bio-active compounds such as drugs, pharmaceutical and cosmetical
`
`ingredients, pesticides, and fungicides.
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`20
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`• Said process for the reduction of the crystallite size, increase of amorphous portion,
`
`change of crystal habit and/or change of crystal polymorphy.
`
`• Said process wherein the protein is a hydrophobin, such as a class II hydrophobin or
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`especially a class I hydrophobin.
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`• Said process wherein precipitation or crystallization of the organic substance is
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`25
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`induced by combining a solution or dispersion thereof with the solution or dispersion
`
`of the amphiphilic protein.
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`• The use of an amphiphilic protein, especially as characterized in any of the
`
`embodiments above, for modifying the morphology and/or polymorphism of an
`
`organic substance.
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`30
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`• A composition comprising a solid organic substance, especially as defined above or
`
`listed farther below, and an amphiphilic protein, especially as characterized in any of
`
`the embodiments above.
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`• Said composition comprising the solid organic substance in the form of fine grain
`
`particles, e.g. of average size 0.1 to 1000 micrometer, or 5 to 5000 nm.
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`

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`WO 2010/003811
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`PCT /EP2009/057760
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`- 11 -
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`The present invention thus includes
`
`• a process for modifying the morphology and/or polymorphism of an organic
`
`substance, which process comprises treating the solid substance, or a solution or
`
`dispersion thereof, with one or more amphiphilic proteins;
`
`5
`
`•
`
`said process, wherein a 1 % b.w. aqueous solution or dispersion of the amphiphilic
`
`protein(s) used is characterized by a contact angle on a polypropylene surface which
`
`is lower than the contact angle observable for pure water by 20 degrees or more;
`
`• any of said processes, which comprises precipitation, crystallization or solid-solid
`
`phase transition of the organic substance; especially for the reduction of the crystallite
`
`10
`
`size, increase of amorphous portion, change of crystal habit and/or change of crystal
`
`polymorphy;
`
`• any of said processes, which comprises i) combining the solution or dispersion of the
`
`protein in a polar solvent, and a solution or dispersion of the organic substance in a
`
`polar solvent which is miscible with the solvent of the protein, or ii) contacting the
`
`15
`
`solution or dispersion of the organic substance in a polar solvent with a surface
`
`impregnated with the protein;
`
`• any of said processes, which comprises wet milling the organic substance in the
`
`presence of the amphiphilic protein(s);
`
`• any of said processes, which comprises the addition of crystal seeds of the organic
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`20
`
`substance to the solution of the organic substance prior to, or after, the addition of the
`
`amphiphilic protein(s);
`
`• any of said processes, wherein a solution contains a further additive such as a salt
`
`and/or a polymer;
`
`• any of said processes, wherein the organic substance is an organic compound, which
`
`25
`
`is solid at 0° Celsius and soluble, partially soluble or dispersable in the polar solvent,
`
`for example as a colloid;
`
`• any of said processes, wherein the organic substance is an organic compound from
`
`the molecular weight range 80 to 1000, especially 100 to 500 g/mol, which is
`
`preferably selected from bio-active compounds such as drugs, pharmaceutical and
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`30
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`cosmetical ingredients, pesticides, and fungicides;
`
`• any of said processes, wherein the protein is a hydrophobin, such as a class II
`
`hydrophobin or especially a class I hydrophobin;
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`PCT /EP2009/057760
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`• any of said processes, wherein precipitation or crystallization of the organic
`
`substance is induced by combining a solution or dispersion thereof with the solution
`
`or dispersion of the amphiphilic protein.
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`5
`
`Present invention further includes the use of an amphiphilic protein, especially as
`
`characterized by lowering of the contact angle as described above, especially a hydrophobin
`
`as described above, for modifying the morphology and/or polymorphism of an organic
`
`substance; as well as a composition comprising a solid organic substance, especially an
`
`organic compound, which is solid at 0° Celsius and soluble, partially soluble or dispersable in
`
`10
`
`the polar solvent, for example as a colloid, and/or an organic compound from the molecular
`
`weight range 80 to 1000, especially 100 to 500 g/mol, which is preferably selected from bio(cid:173)
`
`active compounds such as drugs, pharmaceutical and cosmetical ingredients, pesticides,
`
`and fungicides, in combination with the amphiphilic protein. Said composition preferably
`
`comprises the solid organic substance in the form of fine grain particles.
`
`15
`
`Examples for bio-active organic substances whose solid form may be modified by the
`
`present process include the following ones:
`
`Pharmaceutical ingredients (APls): acarbose, acetylsalicylic acid, alfuzosin, aliskiren,
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`20
`
`ambrisentan, amlodipine, amoxicillin, anastrozole, apixaban, aprepitant, aripiprazole,
`
`atazanavir, atenolol, atomoxetine, atorvastatin, azithromycin, bazedoxifene, benazepril,
`
`bicalutamide, bisacodyl, budesonide, butylscopolamine, candesartan, capecitabine,
`
`carbamazepine, carisbamate, carvedilol, casopitant, celecoxib, cetirizine, chloroquine,
`
`cinacalcet, ciprofloxacin, clavulanic acid, clodronate, clonidine, clopidogrel, cyproterone
`
`25
`
`acetate, dapoxetine, darunavir, dasatinib, deferasirox, dextromethorphan, diclofenac,
`
`dienogest, dipyridamole, docetaxel, donepezil, drospirenone, duloxetine, efavirenz,
`
`eletriptan, enalapril, entacapone, entecavir, enzastaurin, erlotinib, esomeprazole,
`
`eszopiclone, ethinylestradiol, etoricoxib, etravirine, everolismus, exemestane, fexofenadine,
`
`finasteride, fluoxetine, fluticasone, fluticasone propionate, fluvastatin, formoterol, ganciclovir,
`
`30
`
`gefitinib, glimepiride, hydrocodone, ibandronic acid, ibuprofen, indinavir, ipratropium,
`
`irbesartan, lamotrigine, lansoprazole, lapatinib, letrozole, levonorgestrel, linezolid, lisinopril,
`
`losartan, maraviroc, meloxicam, metformin, methylphenidate, metoprolol, moxidectin,
`
`mycophenolic acid, naproxen, nateglinide, nevirapine, nicorandil, nifedipine, nilotinib,
`
`olanzapine, omeprazole, orlistat, oseltamivir, oxaliplatin, oxcarbazepine, paliperidone,
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`pantoprazole, paracetamol, paroxetine, pioglitazone, pramipexole, pravastatin, pregabalin,
`
`quetiapine, rabeprazole, raloxifene, ramipril, reboxetine, risedronate sodium, rivaroxaban,
`
`rivastigmine, rizatriptan, rosiglitazone, ruboxistaurin, salmeterol, sildenafil citrate, simvastatin,
`
`sirolimus, sitagliptin, sorafenib, sumatriptan, sunitinib, surinabant, tadalafil, tamsulosin,
`
`5
`
`tapentadol, telbivudine, telmisartan, terbinafine hydrochloride, teriflunomide, tiotropium,
`
`tolterodine, topiramate, vabicaserin hydrochloride, valaciclovir, valganciclovir, valsartan,
`
`vandetanib, vardenafil, varenicline, venlafaxine, vildagliptin, voriconazole, warfarin,
`
`ziprasidone, zolmitriptan, zolpidem.
`
`10
`
`Further drugs: acepromazine, amoxicillin, ampicillin, apramycin, benazepril, betamethasone,
`
`buscopan, carprofen, cefapirin, clenbuterol, clindamycin, cloxacillin, cyclosporine A,
`
`cyromazine, deracoxib, dichlorvos, dicyclanil, difloxacin, enrofloxacin, etodolac,
`
`fenbendazole, framycetin, furosemide, griseofulvin, hetacillin, hygromycin, imidacloprid,
`
`levamisole, levothyroxine, lufenuron, meloxicam, milbemycin oxime, monensin, moxidectin,
`
`15
`
`narasin, nicarbazin, nitenpyram, oleandomycin, oxfendazole, oxyclozanide, paramectin,
`
`paromomycin, permethrin, phenylbutazone, praziquantel, procaine benzylpenicillin, procaine
`
`penicillin, pyrantel pamoate, spinosad, sulphadiazine, thiamethoxam, tiamulin, triamcinolone,
`
`triclabendazole, trimethoprim, tylosin.
`
`20
`
`Agrochemicals such as pesticides and fungicides: abamectin, brodifacoum, cyromazine,
`
`emamectin, fenoxycarb, pirimicarb, pymetrozine, thiamethoxam.
`
`Cosmetic ingredients such as
`
`UV filter substances (e.g. (+/-)-1,7,7-trimethyl-3-[(4-methylphenyl)methylene]bicyclo-
`
`25
`
`[2.2.1 ]heptan-2-one; 1, 7, 7-trimethyl-3-(phenylmethylene )bicyclo[2.2.1 ]heptan-2-one;
`
`(2-Hydroxy-4-methoxyphenyl)(4-methylphenyl)methanone; 2,4-dihydroxybenzophenone;
`
`2,2',4,4'-tetrahydroxybenzophenone; 2-Hydroxy-4-methoxy benzophenone;
`
`2-Hydroxy-4-methoxy benzophenone-5-sulfonic acid; 2,2'-dihydroxy-4,4'(cid:173)
`
`dimethoxybenzophenone; 2,2'-Dihydroxy-4-methoxybenzophenone; Alpha-(2-oxoborn-3-
`
`30
`
`ylidene )toluene-4-sulphonic acid and its salts; 1-[4-(1, 1-dimethylethyl)phenyl]-3-(4-
`
`methoxyphenyl)propane-1,3-dione; Methyl N, N, N-trimethyl-4-[(4, 7, 7-trimethyl-3-
`
`oxobicyclo[2,2, 1 ]hept-2-ylidene)methyl]anilinium sulphate; 3,3,5-Trimethyl cyclohexyl-2-
`
`hydroxy benzoate; lsopentyl p-methoxycinnamate; Menthyl-o-aminobenzoate; Menthyl
`
`salicylate; 2-Ethylhexyl 2-cyano,3,3-diphenylacrylate; 2- ethylhexyl 4-
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`(dimethylamino)benzoate; 2- ethylhexyl 4- methoxycinnamate; 2- ethylhexyl salicylate;
`
`Benzoic acid, 4, 4', 4"- (1, 3, 5- triazine- 2, 4, 6- triyltriimino)tris-, tris(2-ethylhexyl)ester; 2,4,6-
`
`Trianilino-(p-carbo-2'-ethylhexyl-1 '-oxi)-1,3,5-triazine; 4- aminobenzoic acid; Benzoic acid, 4-
`
`amino-, ethyl ester, polymer with oxirane; 2- phenyl- 1 H- benzimidazole- 5- sulphonic acid;
`
`5
`
`2-Propenamide, N-[[4-[(4, 7, 7-trime