WO2009059605A1 - Small scale solid state screening - Google Patents

Small scale solid state screening Download PDF

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Publication number
WO2009059605A1
WO2009059605A1 PCT/DK2008/000394 DK2008000394W WO2009059605A1 WO 2009059605 A1 WO2009059605 A1 WO 2009059605A1 DK 2008000394 W DK2008000394 W DK 2008000394W WO 2009059605 A1 WO2009059605 A1 WO 2009059605A1
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WO
WIPO (PCT)
Prior art keywords
solid material
receptacle
solid
simulated
secondary manufacturing
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PCT/DK2008/000394
Other languages
French (fr)
Inventor
Jukka Rantanen
Morten ALLESØ
Claus Cornett
Original Assignee
University Of Copenhagen
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Publication of WO2009059605A1 publication Critical patent/WO2009059605A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N25/00—Investigating or analyzing materials by the use of thermal means
    • G01N25/14—Investigating or analyzing materials by the use of thermal means by using distillation, extraction, sublimation, condensation, freezing, or crystallisation
    • G01N25/147—Investigating or analyzing materials by the use of thermal means by using distillation, extraction, sublimation, condensation, freezing, or crystallisation by cristallisation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0072—Crystallisation in microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0077—Screening for crystallisation conditions or for crystal forms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility

Definitions

  • the present invention relates to screening of solid material.
  • the present invention relates to an apparatus and a method for solid state screening of solid material to identify and detect possible solid state forms and phase changes during processing of pharmaceuticals.
  • US 2003/0162226 Al relates to methods for screening hundreds to thousands of samples in parallel, and for determining the conditions and/or ranges of conditions required to produce crystals with desired compositions, particle sizes, habits, or polymorphic forms, i.e. crystallization conditions.
  • US 2004/0219602 Al relates to testing for effects of conditions on a drug sample, in particular as measured over time, i.e. stability measurements.
  • US 2006/0129329 Al relates to investigating different physical and/or chemical forms of a material, subjected to conditions such as heating, cooling, and agitation, which may be used for optimising the physical and chemical properties of a drug candidate in order to select the best candidate for use in clinical trials.
  • WO 2006/078331 A2 relates to a process and an apparatus for transforming a first polymorph of a chemical material into a second polymorph, utilizing an apparatus comprising a vessel connected to a re-circulation system. It discloses examples where at least 250 g of ingredient to be examined is used.
  • phase transformation considerations during process development and manufacture of solid oral dosage forms relate to phase transformations associated with common unit operations on a large scale.
  • An object of the present invention relates to reducing the amount of API necessary during the development phase of new drugs.
  • a further object relates to providing means for screening one or several active ingredients subjected to one or more secondary manufacturing conditions.
  • An additional object relates to providing means for examining phase changes induced by crystallization processes as well as secondary manufacturing processes, preferably by simulating the latter, to avoid using large amounts of the ingredient(s) to be examined.
  • An object is to provide means for automation of the development process.
  • a first aspect of the invention relates to a method for solid state screening by simulating secondary manufacturing of at least one solid material; wherein said solid state screening combines small scale crystallization in a receptacle and the evaluation of any induced phase changes of the solid state material in the same receptacle allowing crystallization and simulated secondary manufacturing to be performed simultaneously or consecutively; and wherein said secondary manufacturing comprises applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material.
  • An additional aspect of the invention relates to simulating the conditions experienced by a solid material, such as an API, an excipient or a composition during secondary manufacturing.
  • An aspect of the invention relates to a method for solid state screening by simulating secondary manufacturing of at least one solid material, wherein said secondary manufacturing is simulated in a step by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, and/or allowing a gas stream to pass over or through said at least one solid material.
  • Another aspect of the present invention relates to an apparatus for providing a way of performing solid state screening of a solid material.
  • the apparatus is arranged for inducing phase changes, i.e. solid state changes, and the solid state changes are induced by crystallization of the solid material and by simulating secondary manufacturing of the solid material.
  • the apparatus comprises a first receptacle for receiving the solid matter and means for inducing crystallization in said solid matter in the first receptacle, and means for processing arranged relative to the first receptacle for simulating secondary manufacturing conditions on said solid material.
  • Another aspect of the present invention relates to an apparatus, which may provide a way of performing at least two kinds of solid material screenings in a single device.
  • This has the advantage that relatively small amount of solid material needs to be provided, and that knowledge of processing induced transitions (PIT) at a relatively early stage of development is obtained.
  • the means for inducing crystallization comprises, and is not limited to, means for inducing crystallization from a melt, and means for inducing crystallization from a solvent.
  • Figure 1 shows Raman spectroscopy measurements of crystallization experiments with theophylline anhydrate.
  • Figure 2 shows the Raman spectra collected from the wet massing and drying studies measured at the end points.
  • Figure 3 shows the near-infrared (NIR) spectra collected from the wet massing and drying studies measured at the end points.
  • NIR near-infrared
  • Figure 4 shows the various elements of the prototype used for expanded solid form screening.
  • Figure 5 shows Raman spectra collected from the milling and compaction studies on nifedipine.
  • Figure 6 shows near-infrared (NIR) measurements of milling experiments with sodium chloride crystals.
  • Figure 7 shows scanning electron micrographs (SEMs) of non-milled (left) and milled (right) sodium chloride crystals.
  • Figure 8 shows a schematic diagram of an apparatus according to the present invention.
  • Figure 9 shows an exploded view of an apparatus according to the present invention.
  • Figure 10 shows a top view of a base part suitable for implementing the present invention.
  • Figure 11 shows three different mechanical processing means according to the present invention.
  • Figure 12 shows a photograph of an apparatus according to the present invention.
  • second manufacturing refers to any process step carried out after synthesis and/or purification of an API and/or an excipient and/or a composition in order to manufacture a final drug composition.
  • simulated secondary manufacturing refers to secondary manufacturing process steps mimicked or carried out on a smaller scale than actual pilot or manufacturing scale.
  • solid state screening is used herein to refer to examination or measurement of crystalline or amorphous phases.
  • a crystalline phase may be any crystal form of a pure API or an excipient, as well as any salt form, co-crystal form, and/or solvate form of the API or excipient.
  • phase change is used to refer to any type of change of the molecular arrangement of API or excipient molecules of a solid material. Phase changes may occur during crystallization or during secondary manufacturing.
  • high-throughput polymorph screening refers to polymorph screening, wherein a large number of samples are subjected to the screening.
  • solid material refers to any material, which is present as solid matter at any time during any process step before being part of a final drug product.
  • API refers to an active pharmaceutical ingredient.
  • excipient refers to any auxiliary ingredient differing from an API of a particular final drug product.
  • composition refers to any API and/or excipient, including any combination of any number of these.
  • crystalstallization refers to a phase transition from liquid to solid state, such as precipitation, hardening or congealment.
  • receptacle may be any chamber or receptacle, which is suitable for crystallisation and subsequent simulation of secondary manufacturing.
  • small scale is used herein about a scale smaller than pilot scale, such as when a receptacle comprises an amount of API and/or excipient, which is less than about 2 g, more preferred less than 1 g, and may refer to an effective single dosage for administration for a therapeutic or prophylactic purpose.
  • an embodiment of the invention relates to a method according to the invention comprising the steps of: a. Providing a liquid in a receptacle, said liquid comprising at least one API or excipient; b. Crystallization by allowing said at least one API or excipient to solidify, for example by precipitation or congealing, forming said at least one solid material; c. Simulating secondary manufacturing by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material in said receptacle and d. Screening by measurement of the crystalline state of said at least one solid state material.
  • An embodiment of the invention relates to a method according to the invention, wherein said secondary manufacturing is simulated by a compaction step.
  • An embodiment of the invention relates to a method according to the invention, wherein said secondary manufacturing is simulated by a milling step, preferably before a subsequent compaction step.
  • An embodiment of the invention relates to a method according to the invention, wherein said secondary manufacturing is simulated by a wet massing step followed by a drying step, preferably before a subsequent compaction step.
  • An embodiment of the invention relates to a method according to the invention, wherein said wet massing step followed by said drying step, is followed by a subsequent milling step.
  • An embodiment of the invention relates to a method according to the invention, wherein a milling step is followed by said wet massing step.
  • An embodiment of the invention relates to a method according to the invention, wherein said secondary manufacturing is simulated in a step a) by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material.
  • a method according to the invention comprises secondary manufacturing which is further simulated in a step b) by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material, subsequent to a step a), wherein step b) is different from said step a).
  • Step a) refers to applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, and/or allowing a gas stream to pass over or through said at least one solid material
  • secondary manufacturing is further simulated in a number of steps by applying at least one of the conditions of heating, cooling, pressure, strain, stress and/or shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material, wherein each step is different from the previous step.
  • Another preferred embodiment comprises secondary manufacturing simulating at least one of blending, wetting, wet massing, drying, granulation, milling, compaction, compression, tableting, coating, spray drying and freeze drying.
  • Wet granulation may be low/high shear wet granulation.
  • the method according to the invention comprises milling, simulated by introducing mechanical stress in order to reduce the particle size of the solid material.
  • the method according to the invention comprises wet massing simulated by adding a liquid to said at least one solid material followed by applying shear forces by contacting said at least one solid material and said liquid to a rotating, uneven surface. Alternatively, application of shear forces may be followed by addition of liquid.
  • the method according to the invention comprises simulating tableting by applying pressure to the solid material in order to reduce the volume of the solid material.
  • the method according to the invention comprises at least one solid material that is subjected to the conditions of said simulated second manufacturing in an amount of less than a value selected among 100 g, 50 g, 20 g, 10 g, 5 g, 2 g, 1 g, 500 mg, 300 mg, 200 mg, 100 mg, 50 mg, 25 mg, 10 mg, 5 mg, 2 mg, 1 mg, 500 ⁇ g, 300 ⁇ g, 200 ⁇ g, 100 ⁇ g, 50 ⁇ g, 25 ⁇ g, 10 ⁇ g, 5 ⁇ g, 2 ⁇ g, and 1 ⁇ g, in a chamber or receptacle.
  • the amount is less than about 3 g, more preferred less than 2 g, preferably less than 1 g in a chamber or receptacle.
  • the method according to the invention comprises said solid state screening, combining small scale crystallization and the evaluation of induced solid state changes induced by the application of stress, simulating conditions encountered during secondary manufacturing, preferably in the same chamber or receptacle, allowing crystallization and simulated secondary manufacturing to be performed simultaneously or consecutively.
  • the method according to the invention comprises said at least one solid material which is selected among an API, an excipient or a composition.
  • a method according to the invention comprises at least one solid material which is an API for oral, dermal, topical, respiratory, intravenous, intraperitoneal, rectal, vaginal, occual, nasal, or buccal administration.
  • a method according to the invention comprises at least one solid material which is solubilised in an aqueous medium before crystallization.
  • the method according to the invention comprises solid state screening comprising comparing between at least two different crystal forms of at least one solid material selected among a co-crystal form, a solvate form and a derivative, such as a salt or an ester.
  • the method according to the invention comprises high- throughput solid state screening, wherein multiple samples of said at least one solid material are subjected to varying degrees of simulated secondary manufacturing processes and experimental results are gathered, processed and organized in a computer.
  • the method according to the invention comprises high- throughput solid state screening, wherein multiple samples of different solid materials are subjected to at least one simulated secondary manufacturing process and the measurement results are gathered in a computer.
  • the method according to the invention comprises a number of samples of said at least one solid material subjected to at least one simulated secondary manufacturing processes which is at least 2, 4, 6, 8, 10, 16, 32, 64, 128, 256, 512 or 1024.
  • the method according to the invention comprises at least one solid material which is subjected to at least a number of simulated secondary manufacturing conditions selected among 2, 4, 6, 8, 10, 16, 32, 64, 128, 256, 512 and 1024; whereby a number of unit operations selected among 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 are simulated.
  • Unit operations may comprise size reduction, wet granulation, dry granulation, direct compression, melt granulation, spray drying, freeze drying, tabletting and capsule filling. Some unit operations and possible relations between them are further described in Zhang (2004), p. 279, Fig. 4.
  • Wet granulation may comprise mixing/dissolving/suspending; drying; milling/size adjusting; and blending.
  • Dry granulation may comprise blending, compacting, milling/size adjusting; and blending.
  • Direct compression may comprise blending.
  • Melt granulation may comprise m ⁇ xing/melting/dissolving; congealing; milling/size adjusting; and blending.
  • Spray drying may comprise dissolving/suspending; spraying/drying; and blending.
  • Freeze drying may comprise dissolving; freezing; vacuum/drying; and blending. Tabletting may comprise compacting; coating; dissolving/suspending; and spraying/drying.
  • a method according to the invention comprises solid state changes of said at least one solid material identified by at least one of infrared (IR) spectroscopy, near-infrared (NIR) spectroscopy, Raman spectroscopy, terahertz pulsed spectroscopy (TPS), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), microcalorimetry, solution calorimetry, X-ray powder diffractometry (XRPD), Single crystal X-ray diffractometry (XRD), optical microscopy, Scanning Electron Microscopy (SEM), solvent sorption/desorption analysis, and solid state NMR.
  • IR infrared
  • NIR near-infrared
  • NIR near-infrared
  • Raman spectroscopy Raman spectroscopy
  • TPS terahertz pulsed spectroscopy
  • DSC Differential Scanning Calorimetry
  • TGA Differential Scanning Calorimetry
  • a method according to the invention comprises examining solid state changes induced by simulated secondary manufacturing wherein small-scale samples, according to the invention, are subjected to at least one of the simulated processes according to the invention, and the solid state changes are measured according to the invention.
  • an apparatus comprises processing means that are arranged for performing a unit operation, or parts thereof, comprising at least one of size reduction, wet granulation, dry granulation, direct compression, melt granulation, spray drying, freeze drying, tabletting, and capsule filling.
  • the processing means of an apparatus may perform various unit operations.
  • unit operations For more details on unit operations, the reader is referred to "Phase transformation considerations during process development and manufacture of solid oral dosage forms", Advanced Drug Delivery Reviews 56 (2004) 371-390, Geoff G. Z. Zhang et al. ("Zhang (2004)”), which is hereby incorporated by reference in its entirety.
  • an apparatus comprises the processing means comprising mechanical processing means capable of simulating mechanical stresses during secondary manufacturing of the solid material in a drug formulation.
  • an apparatus comprises said mechanical processing means that are capable of subjecting a main portion of the solid material in the first receptacle to said mechanical stresses substantially simultaneous.
  • an apparatus according to the invention comprises the main portion of the solid material which constitutes at least 60%, preferably at least 70%, more preferably at least 80%, or most preferably at least 90% of the solid material receivable in the first receptacle.
  • an apparatus comprises the processing means comprising a miller, such as a ball miller, receivable in the first receptacle.
  • a miller such as a ball miller
  • an apparatus comprises the processing means comprising a compaction device, such as a compression punch, receivable in the first receptacle.
  • a compaction device such as a compression punch
  • an apparatus comprises the processing means comprising a wet massing device receivable in the first receptacle.
  • an apparatus further comprises a second receptacle for receiving the solid material, the means for inducing crystallization in the solid matter being in thermal contact with the second receptacle, and further processing means being arranged relative to the second receptacle for simulating secondary manufacturing conditions on the solid material.
  • an apparatus comprises the internal volume of the first receptacle and/or the second receptacle which is maximum ca. 100 mL, maximum ca. 50 ml_, maximum ca. 10 ml_, maximum ca. 1 mL, maximum ca. 100 ⁇ l_, or maximum ca. 10 ⁇ L.
  • a receptacle of an apparatus according to the present invention may have a certain maximum volume. This is particular advantageous because conventional solid state screening during second manufacturing typically requires an amount of the solid material being in the order of kilograms, which is an amount that can be costly to obtain, especially for a newly developed active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • an apparatus comprises the processing means arranged relative to the first and the second receptacle so as to subject the solid matter to two different kinds of simulations conditions.
  • an apparatus comprises the first receptacle arranged to house an internal optical monitoring probe.
  • an apparatus comprises the means for inducing crystallization comprising heating means in thermal contact with the first receptacle, and/or cooling means in thermal contact with the first receptacle.
  • Figure 2 shows the Raman spectra collected from the wet massing and drying studies measured at the end points. Theophylline anhydrate was used as starting material in the wet massing experiment, while the monohydrate was exposed to drying.
  • Figure 3 shows the NIR spectra collected from the wet massing and drying studies measured at the end points. Theophylline anhydrate was used as starting material in the wet massing experiment, while the monohydrate was exposed to drying.
  • Figure 4 shows the various elements of the prototype used for expanded solid form screening.
  • Left hand side The 2x2 well-plate chassis with the inclusion of four vials.
  • the primary unit is built out of aluminum while each vial is made out of stainless steel.
  • Right hand side Small scale processing equipment made out of stainless steel. Active heating/cooling of the vials can be performed using a circulating water bath (Ecoline RE106; Lauda Brinkmann, Westbury, NY) with attached thermostat (Ecoline ElOO; Lauda Brinkmann, Westbury, NY).
  • the temperature of the primary well-plate unit can be monitored using a thermo sensor (ama-digit ad 15th, Germany) inserted into the center of the unit.
  • the basic principle of the modular CryProc unit is that it can easily be expanded to the desired size.
  • Figure 5 shows Raman spectra collected from the milling and compaction studies. Amorphous nifedipine was used as starting material for both types of unit operations.
  • Figure 8 is a schematic diagram of an apparatus according to the present invention for solid state screening of a solid material SIM.
  • the apparatus is arranged for inducing solid state transitions in the solid material by at least two different ways.
  • the solid state transitions may be induced by crystallization of the solid material.
  • the crystallization may be e.g. crystallization from a solution or a crystallization from a melt.
  • the solid state transitions may be induced by simulating secondary manufacturing of the solid material SM.
  • the solid state screening may, in particular, comprise monitoring of solid state transitions i.e. phase or structural changes.
  • the apparatus comprises a first receptacle 10 for receiving the solid material SM.
  • the receptacle 10 can be detachably mounted on the base part 20 or it can form an integral part of the base part 20.
  • the base part 20 comprises means for inducing crystallization in the solid material SM in the first receptacle 10 i.e. the means for inducing crystallization may comprise heating means in thermal contact with the first receptacle 10, and/or cooling means in thermal contact with the first receptacle 10 as will be explained in more detail below in connection with Figures 9 and 10.
  • a second receptacle 11 is also schematically indicated in Figure 8.
  • the teaching of the present invention can be extended to two, three, four etc. receptacles arranged on a common base part 20.
  • Such a plurality or array of receptacles can be particular advantageous for high-throughput testing and development of one or more different kind of solid material SM, and/or with one or more processing conditions simulating secondary manufacturing.
  • the apparatus also comprises processing means 15 arranged relative to the first receptacle 10 for simulating secondary manufacturing conditions on the solid matter SM.
  • the processing means 15 may be simulating any kind of processing during secondary manufacturing i.e. unit operations, or parts thereof, like size reduction, wet granulation, dry granulation, direct compression, melt granulation, spray drying, freeze drying, tabletting, and capsule filling.
  • the processing means 15 has been drawn in Figure 8 as a mechanical processing means i.e. a compaction device such as a compression punch or die.
  • the simulated secondary manufacturing refers in this context to secondary manufacturing process steps carried out on a smaller scale than actual pilot or manufacturing scale.
  • the first receptacle 10 may be arranged to house an internal optical monitoring probe (not shown in Figure 8), e.g. Raman or NIR can be performed via an optical fibre/probe connected to the receptacle 10. The monitoring or measurements can however also be performed outside the receptacle 10.
  • Figure 9 is an exploded cross-sectional view of an apparatus according to the present invention showing two different kind of mechanical processing means i.e. a compaction device such as a compression punch or die 15a and wet massing device 15b.
  • the processing means 15a and 15b are adapted to be received in the first 10 and the second 11 receptacle, respectively.
  • Components for punching the die 15a and combined pressing and rotating of the wet massing device 15b, respectively, are not shown for clarity in the Figure, but standard components like power drills and compaction or compression devices can be utilised for that purpose.
  • the base part 20 comprises cooling means i.e. cooling ribs 21 and heating/cooling means i.e. conduction means 22 for flowing fluid, e.g. water, through the base part 20.
  • cooling means i.e. cooling ribs 21
  • heating/cooling means i.e. conduction means 22 for flowing fluid, e.g. water
  • Figure 10 shows a top view of the base part 20 shown in Figure 9, the base part
  • the base part 20 being suitable for implementing the present invention.
  • the base part 20 functions from a thermal point of view essentially as a heat sink with cooling ribs
  • the heat capacity of the base part 20 should therefore be substantially larger than the combined heat capacity of receptacle and the one or more receptacles 10, 11, 12 and 13.
  • the dimensions of the base part 20 should accordingly be proportionated relative to the one or more receptacles 10, 11, 12, and 13.
  • the internal volume of the first receptacle 10 and the second receptacle 11 may be maximum ca. 100 ml_, preferably maximum ca. 50 ml_, or most preferably maximum ca. 10 ml_.
  • the base part can be made in stainless steel (SS), or other suitable heat conduction material, with a cooling rib frame having outer dimensions ca. 27 x 95x 140 mm, cf. Figure 9, and a top portion of the base part 20 having outer dimensions ca. 30 x 70 x 70 mm, cf. Figure 9.
  • Thermal monitoring can be performed by one or more thermal probes (not shown in Figure 10) integrated in or on the base part 20.
  • Figure 11 shows three different mechanical processing means 15a, 15b, and 15c for performing unit operations that simulate second manufacturing conditions, the means are seen from both a side view (top) and an end view (bottom).
  • the compaction device (the compression punch) 15a is shown without a rear piece for making the mechanical connection to the punch actuator.
  • the wet massing device 15b is similarly shown without the closing top section.
  • the ball miller 15c comprises seven spherical protrusions as seen in the end view but any number of protrusions can be used.
  • Figure 12 shows a photograph of an apparatus according to the present invention.
  • the apparatus comprises three mechanical processing means; a compaction device (compression punch) 15a, a wet massing device 15b, and a ball-miller 15c, each mechanical processing means being received in the corresponding receptacles 12, 10, and 11, respectively.
  • the fourth receptacle 13 is used for reference measurements.
  • a suitable amount of 1) was transferred to each of the four vials. 2.50 ml of each solvent, 2)-5), was separately added to a vial. The slurries were then heated to approx. 60 0 C followed by cooling to ambient temperature. Heating/cooling of the device was done using a circulating water bath (Ecoline RE106; Lauda Brinkmann, Westbury, NY) and attached thermostat (Ecoline ElOO; Lauda Brinkmann, Westbury, NY). Solvents 3)-5) were evaporated after cooling whereas solvent 2) was removed by filtering.
  • the solid-state of the recrystallized yield from each of the four vials was investigated by Raman spectroscopy (5 cm-1 resolution; Control Development, Inc., South Bend, IN) with a fiber optic probe (laser spot size 90 ⁇ m, focal length 5 mm; InPhotonics, Norwood, MA) and a diode laser (wavelength 785 nm; Starbright 785 S, Torsana Laser Technologies, Denmark) and a thermoelectrically cooled 2DMPP charge coupled device (CCD) (1024 x 64) detector (Control Development, Inc., South Bend, IN, USA).
  • Raman spectroscopy 5 cm-1 resolution; Control Development, Inc., South Bend, IN
  • a fiber optic probe laser spot size 90 ⁇ m, focal length 5 mm; InPhotonics, Norwood, MA
  • a diode laser wavelength 785 nm; Starbright 785 S, Torsana Laser Technologies, Denmark
  • CCD thermoelectrically cooled 2DMPP charge coupled device
  • a suitable amount of 1) was transferred to a single vial.
  • the solid state of the starting material was verified by Raman (see above) and near-infrared (NIR) spectroscopy (Control Development Inc., South Bend, IN) with a fiber optic probe, a tungsten light source and a thermoelectrically cooled InGaAs diode array detector. Each NIR spectrum was the average of 32 scans with a 10 milliseconds integration time.
  • the wet massing device was attached to a power drill (Type SB.25, Holstebro Jernst ⁇ beri & Maskinfabrik, Denmark) and stirring of 1) was commenced at 1290 RPM. Immediately thereafter and during stirring, approx. 50 ⁇ l of 2) was added. Wet massing time was 2 minutes. The existence of granules was visually observed.
  • a suitable amount of theophylline monohydrate crystals produced from 1) was transferred to a vial and kept at 60 0 C for 50 min.
  • the solid-state of the starting material i.e. prior to drying
  • the temperature in the center of the prototype unit was continuously monitored and kept at 60.5 0 C.
  • the solid-state was monitored every 30 seconds using Raman and NIR spectroscopy (see above) until reaching the end point after 50 min.
  • Raman and NIR data at the end-point are presented in Figure 2 and 3, respectively.
  • the spectra confirm the transformation of the monohydrate form into the anhydrate form, verifying that theophylline monohydrate is physically unstable towards heat.
  • nifedipine was verified by Raman spectroscopy (see below) using the reference spectra provided by Chan et al. (Polymorphism and devitrification of nifedipine under controlled humidity: a combined FT-Raman, IR and Raman microscopic investigation. J Raman Spectrosc. 2004, 35:353-359).
  • Amorphous nifedipine was prepared by melting 1) at approximately 185°C and then quenching the melt on the ice. 30 mg of amorphous nifedipine was transferred to a single vial. Three balls (see Figure 4), corresponding to a ball to mass ratio of 50: 1, were added to the vial and the vial was sealed shut with a lid. Small-scale milling was simulated by shaking the vial on a vortex mixer at approximately 2500 shakes min-1 (speed 4.5). Milling was performed at room temperature (19 ⁇ I 0 C), and no significant temperature increase was detected at the end of the milling (20 minutes).
  • CCD Charge Coupled Device
  • Milled material (see above) was compacted directly in a single sample cup using the punch designed for CryProc and a manual hydraulic press (Perkin-Elmer,

Abstract

The present invention relates to screening of solid material. In particular the present invention relates to an apparatus and a method for screening of crystalline or amorphous material during secondary manufacturing. Accordingly the invention relates to a method for solid state screening by simulating secondary manufacturing of at least one solid material; wherein said solid state screening combines small scale crystallization in a receptacle and the evaluation of induced solid state changes in said receptacle, allowing crystallization and simulated secondary manufacturing to be performed simultaneously or consecutively; and wherein said secondary manufacturing comprises applying at least one of the conditions of strain, stress, and/or shear forces.

Description

Small Scale Solid State Screening
Technical field of the invention
The present invention relates to screening of solid material. In particular the present invention relates to an apparatus and a method for solid state screening of solid material to identify and detect possible solid state forms and phase changes during processing of pharmaceuticals.
Background of the invention In general methods exist for solid state screening and examining phase changes during secondary manufacturing using large amounts of solid material, and systematic methods for inducing phase changes in a given solid material.
US 2003/0162226 Al relates to methods for screening hundreds to thousands of samples in parallel, and for determining the conditions and/or ranges of conditions required to produce crystals with desired compositions, particle sizes, habits, or polymorphic forms, i.e. crystallization conditions.
US 2004/0219602 Al relates to testing for effects of conditions on a drug sample, in particular as measured over time, i.e. stability measurements.
US 2006/0129329 Al relates to investigating different physical and/or chemical forms of a material, subjected to conditions such as heating, cooling, and agitation, which may be used for optimising the physical and chemical properties of a drug candidate in order to select the best candidate for use in clinical trials.
WO 2006/078331 A2 relates to a process and an apparatus for transforming a first polymorph of a chemical material into a second polymorph, utilizing an apparatus comprising a vessel connected to a re-circulation system. It discloses examples where at least 250 g of ingredient to be examined is used.
The article "Pellet Manufacturing by Extrusion-Spheronization Using Process Analytical Technology", AAPS PharmaSciTech 2005; 6(2) Article 26, E174, by Niklas Sandler et al., investigates phase transitions during extrusion- spheronization. These researchers used batch sizes of 2000 g.
The article "Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes", Advanced Drug Delivery Reviews 48 (2001) 91-114, Kenneth R. Morris et al., provides theoretical insights into the title theme.
The article "Effects of Mechanical Processing on Phase Composition", J. Pharmaceutical Scienes, Vol. 91, No. 7, July 2002, describes inter alia how a hard crystalline drug substance surrounded by softer excipients may be affected by milling and compression.
The article "Phase transformation considerations during process development and manufacture of solid oral dosage forms", Advanced Drug Delivery Reviews 56 (2004) 371-390, Geoff G. Z. Zhang et al. ("Zhang (2004)"), relates to phase transformations associated with common unit operations on a large scale.
Summary of the invention There exists a need in the pharmaceutical industry to reduce costs during the development phase of new drugs and new dosage forms, e.g. by reducing the time and resources necessary to optimise secondary manufacturing. Usually, secondary manufacturing is initiated at a relatively late stage in the development process, and requires large amount of API (active pharmaceutical ingredient), which may particularly costly if the API is recently developed.
The development of pharmaceutical formulations often requires a substantial amount of manual labour, which may lead to poor reproducibility.
There exists a desire for identifying as many solid forms of a drug candidate as possible, preferably all forms. This would decrease the risk of 'disappearing' polymorphs after launch of a drug, thus avoiding undesirable changes to drug product performance. Further, the identification of different solid forms of a drug may greatly aid in decision-making when choosing the optimal solid form for development. Additional advantages may be the potential identification of high- risk unit operations already at the stage of pre-formulation. This could provide knowledge support for subsequently choosing the right processing equipment.
Hence, an improved method for investigating solid state changes of API's and excipients during secondary manufacturing would be advantageous, and in particular a more efficient method would be advantageous.
An object of the present invention relates to reducing the amount of API necessary during the development phase of new drugs. A further object relates to providing means for screening one or several active ingredients subjected to one or more secondary manufacturing conditions. An additional object relates to providing means for examining phase changes induced by crystallization processes as well as secondary manufacturing processes, preferably by simulating the latter, to avoid using large amounts of the ingredient(s) to be examined.
An object is to provide means for automation of the development process.
In particular, it is an object of the present invention to provide a method for screening a high number of samples that solves the above mentioned problems of the prior art without the need of large amounts of API or excipient(s).
Accordingly, a first aspect of the invention relates to a method for solid state screening by simulating secondary manufacturing of at least one solid material; wherein said solid state screening combines small scale crystallization in a receptacle and the evaluation of any induced phase changes of the solid state material in the same receptacle allowing crystallization and simulated secondary manufacturing to be performed simultaneously or consecutively; and wherein said secondary manufacturing comprises applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material..
An additional aspect of the invention relates to simulating the conditions experienced by a solid material, such as an API, an excipient or a composition during secondary manufacturing. An aspect of the invention relates to a method for solid state screening by simulating secondary manufacturing of at least one solid material, wherein said secondary manufacturing is simulated in a step by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, and/or allowing a gas stream to pass over or through said at least one solid material.
Another aspect of the present invention relates to an apparatus for providing a way of performing solid state screening of a solid material. The apparatus is arranged for inducing phase changes, i.e. solid state changes, and the solid state changes are induced by crystallization of the solid material and by simulating secondary manufacturing of the solid material. The apparatus comprises a first receptacle for receiving the solid matter and means for inducing crystallization in said solid matter in the first receptacle, and means for processing arranged relative to the first receptacle for simulating secondary manufacturing conditions on said solid material.
Another aspect of the present invention relates to an apparatus, which may provide a way of performing at least two kinds of solid material screenings in a single device. This has the advantage that relatively small amount of solid material needs to be provided, and that knowledge of processing induced transitions (PIT) at a relatively early stage of development is obtained. It should be noted that the means for inducing crystallization comprises, and is not limited to, means for inducing crystallization from a melt, and means for inducing crystallization from a solvent.
Brief description of the figures
The figures are briefly described below.
Figure 1 shows Raman spectroscopy measurements of crystallization experiments with theophylline anhydrate.
Figure 2 shows the Raman spectra collected from the wet massing and drying studies measured at the end points. Figure 3 shows the near-infrared (NIR) spectra collected from the wet massing and drying studies measured at the end points.
Figure 4 shows the various elements of the prototype used for expanded solid form screening.
Figure 5 shows Raman spectra collected from the milling and compaction studies on nifedipine.
Figure 6 shows near-infrared (NIR) measurements of milling experiments with sodium chloride crystals.
Figure 7 shows scanning electron micrographs (SEMs) of non-milled (left) and milled (right) sodium chloride crystals.
Figure 8 shows a schematic diagram of an apparatus according to the present invention.
Figure 9 shows an exploded view of an apparatus according to the present invention.
Figure 10 shows a top view of a base part suitable for implementing the present invention.
Figure 11 shows three different mechanical processing means according to the present invention.
Figure 12 shows a photograph of an apparatus according to the present invention.
The present invention will now be described in more detail in the following.
Detailed description of the invention
Prior to discussing the present invention in further details, the following terms and conventions will first be defined: In the present context, the term "secondary manufacturing" refers to any process step carried out after synthesis and/or purification of an API and/or an excipient and/or a composition in order to manufacture a final drug composition.
As used herein, the term "simulated secondary manufacturing" refers to secondary manufacturing process steps mimicked or carried out on a smaller scale than actual pilot or manufacturing scale.
The term "solid state screening" is used herein to refer to examination or measurement of crystalline or amorphous phases. A crystalline phase may be any crystal form of a pure API or an excipient, as well as any salt form, co-crystal form, and/or solvate form of the API or excipient.
The term "phase change" is used to refer to any type of change of the molecular arrangement of API or excipient molecules of a solid material. Phase changes may occur during crystallization or during secondary manufacturing.
In the present context, the term "high-throughput polymorph screening" refers to polymorph screening, wherein a large number of samples are subjected to the screening.
As used herein, the term "solid material" refers to any material, which is present as solid matter at any time during any process step before being part of a final drug product.
The term "API" as used herein refers to an active pharmaceutical ingredient.
In the present context, the term "excipient" refers to any auxiliary ingredient differing from an API of a particular final drug product.
As used herein, the term "composition" refers to any API and/or excipient, including any combination of any number of these. In the present context, the term "crystallization" refers to a phase transition from liquid to solid state, such as precipitation, hardening or congealment.
As used herein, the term "receptacle" may be any chamber or receptacle, which is suitable for crystallisation and subsequent simulation of secondary manufacturing.
The term "small scale" is used herein about a scale smaller than pilot scale, such as when a receptacle comprises an amount of API and/or excipient, which is less than about 2 g, more preferred less than 1 g, and may refer to an effective single dosage for administration for a therapeutic or prophylactic purpose.
Accordingly, an embodiment of the invention relates to a method according to the invention comprising the steps of: a. Providing a liquid in a receptacle, said liquid comprising at least one API or excipient; b. Crystallization by allowing said at least one API or excipient to solidify, for example by precipitation or congealing, forming said at least one solid material; c. Simulating secondary manufacturing by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material in said receptacle and d. Screening by measurement of the crystalline state of said at least one solid state material.
An embodiment of the invention relates to a method according to the invention, wherein said secondary manufacturing is simulated by a compaction step.
An embodiment of the invention relates to a method according to the invention, wherein said secondary manufacturing is simulated by a milling step, preferably before a subsequent compaction step.
An embodiment of the invention relates to a method according to the invention, wherein said secondary manufacturing is simulated by a wet massing step followed by a drying step, preferably before a subsequent compaction step.
An embodiment of the invention relates to a method according to the invention, wherein said wet massing step followed by said drying step, is followed by a subsequent milling step. An embodiment of the invention relates to a method according to the invention, wherein a milling step is followed by said wet massing step.
An embodiment of the invention relates to a method according to the invention, wherein said secondary manufacturing is simulated in a step a) by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material.
In one embodiment, a method according to the invention comprises secondary manufacturing which is further simulated in a step b) by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material, subsequent to a step a), wherein step b) is different from said step a). Step a) refers to applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, and/or allowing a gas stream to pass over or through said at least one solid material
In a preferred embodiment, secondary manufacturing is further simulated in a number of steps by applying at least one of the conditions of heating, cooling, pressure, strain, stress and/or shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material, wherein each step is different from the previous step.
Another preferred embodiment comprises secondary manufacturing simulating at least one of blending, wetting, wet massing, drying, granulation, milling, compaction, compression, tableting, coating, spray drying and freeze drying.
Wet granulation may be low/high shear wet granulation.
In an embodiment, the method according to the invention comprises milling, simulated by introducing mechanical stress in order to reduce the particle size of the solid material. In another embodiment, the method according to the invention comprises wet massing simulated by adding a liquid to said at least one solid material followed by applying shear forces by contacting said at least one solid material and said liquid to a rotating, uneven surface. Alternatively, application of shear forces may be followed by addition of liquid.
In yet another embodiment, the method according to the invention comprises simulating tableting by applying pressure to the solid material in order to reduce the volume of the solid material.
In a preferred embodiment, the method according to the invention comprises at least one solid material that is subjected to the conditions of said simulated second manufacturing in an amount of less than a value selected among 100 g, 50 g, 20 g, 10 g, 5 g, 2 g, 1 g, 500 mg, 300 mg, 200 mg, 100 mg, 50 mg, 25 mg, 10 mg, 5 mg, 2 mg, 1 mg, 500 μg, 300 μg, 200 μg, 100 μg, 50 μg, 25 μg, 10 μg, 5 μg, 2 μg, and 1 μg, in a chamber or receptacle. Preferably, the amount is less than about 3 g, more preferred less than 2 g, preferably less than 1 g in a chamber or receptacle.
In another preferred embodiment, the method according to the invention comprises said solid state screening, combining small scale crystallization and the evaluation of induced solid state changes induced by the application of stress, simulating conditions encountered during secondary manufacturing, preferably in the same chamber or receptacle, allowing crystallization and simulated secondary manufacturing to be performed simultaneously or consecutively.
In yet another preferred embodiment, the method according to the invention comprises said at least one solid material which is selected among an API, an excipient or a composition.
In an embodiment, a method according to the invention comprises at least one solid material which is an API for oral, dermal, topical, respiratory, intravenous, intraperitoneal, rectal, vaginal, occual, nasal, or buccal administration. In another embodiment, a method according to the invention comprises at least one solid material which is solubilised in an aqueous medium before crystallization.
In yet another embodiment, the method according to the invention comprises solid state screening comprising comparing between at least two different crystal forms of at least one solid material selected among a co-crystal form, a solvate form and a derivative, such as a salt or an ester.
In an embodiment, the method according to the invention comprises high- throughput solid state screening, wherein multiple samples of said at least one solid material are subjected to varying degrees of simulated secondary manufacturing processes and experimental results are gathered, processed and organized in a computer.
In another embodiment, the method according to the invention comprises high- throughput solid state screening, wherein multiple samples of different solid materials are subjected to at least one simulated secondary manufacturing process and the measurement results are gathered in a computer.
In yet another embodiment, the method according to the invention comprises a number of samples of said at least one solid material subjected to at least one simulated secondary manufacturing processes which is at least 2, 4, 6, 8, 10, 16, 32, 64, 128, 256, 512 or 1024.
In another embodiment, the method according to the invention comprises at least one solid material which is subjected to at least a number of simulated secondary manufacturing conditions selected among 2, 4, 6, 8, 10, 16, 32, 64, 128, 256, 512 and 1024; whereby a number of unit operations selected among 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 are simulated.
Unit operations may comprise size reduction, wet granulation, dry granulation, direct compression, melt granulation, spray drying, freeze drying, tabletting and capsule filling. Some unit operations and possible relations between them are further described in Zhang (2004), p. 279, Fig. 4. Wet granulation may comprise mixing/dissolving/suspending; drying; milling/size adjusting; and blending. Dry granulation may comprise blending, compacting, milling/size adjusting; and blending. Direct compression may comprise blending. Melt granulation may comprise mϊxing/melting/dissolving; congealing; milling/size adjusting; and blending. Spray drying may comprise dissolving/suspending; spraying/drying; and blending. Freeze drying may comprise dissolving; freezing; vacuum/drying; and blending. Tabletting may comprise compacting; coating; dissolving/suspending; and spraying/drying.
In an embodiment, a method according to the invention comprises solid state changes of said at least one solid material identified by at least one of infrared (IR) spectroscopy, near-infrared (NIR) spectroscopy, Raman spectroscopy, terahertz pulsed spectroscopy (TPS), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), microcalorimetry, solution calorimetry, X-ray powder diffractometry (XRPD), Single crystal X-ray diffractometry (XRD), optical microscopy, Scanning Electron Microscopy (SEM), solvent sorption/desorption analysis, and solid state NMR.
Further relevant analytical methods for the present invention are described in Zhang (2004), p. 377, table 2.
Further, in another embodiment, a method according to the invention comprises examining solid state changes induced by simulated secondary manufacturing wherein small-scale samples, according to the invention, are subjected to at least one of the simulated processes according to the invention, and the solid state changes are measured according to the invention.
In yet another embodiment, an apparatus according to the invention comprises processing means that are arranged for performing a unit operation, or parts thereof, comprising at least one of size reduction, wet granulation, dry granulation, direct compression, melt granulation, spray drying, freeze drying, tabletting, and capsule filling.
The processing means of an apparatus according to the present invention may perform various unit operations. For more details on unit operations, the reader is referred to "Phase transformation considerations during process development and manufacture of solid oral dosage forms", Advanced Drug Delivery Reviews 56 (2004) 371-390, Geoff G. Z. Zhang et al. ("Zhang (2004)"), which is hereby incorporated by reference in its entirety.
In an embodiment, an apparatus according to the invention comprises the processing means comprising mechanical processing means capable of simulating mechanical stresses during secondary manufacturing of the solid material in a drug formulation.
In another embodiment, an apparatus according to the invention comprises said mechanical processing means that are capable of subjecting a main portion of the solid material in the first receptacle to said mechanical stresses substantially simultaneous.
In yet another embodiment, an apparatus according to the invention comprises the main portion of the solid material which constitutes at least 60%, preferably at least 70%, more preferably at least 80%, or most preferably at least 90% of the solid material receivable in the first receptacle.
In a particular embodiment, an apparatus according to the invention comprises the processing means comprising a miller, such as a ball miller, receivable in the first receptacle.
In yet another particular embodiment, an apparatus according to the invention comprises the processing means comprising a compaction device, such as a compression punch, receivable in the first receptacle.
In a noteworthy embodiment, an apparatus according to the invention comprises the processing means comprising a wet massing device receivable in the first receptacle.
In another noteworthy embodiment, an apparatus according to the invention further comprises a second receptacle for receiving the solid material, the means for inducing crystallization in the solid matter being in thermal contact with the second receptacle, and further processing means being arranged relative to the second receptacle for simulating secondary manufacturing conditions on the solid material.
In yet another noteworthy embodiment, an apparatus according to the invention comprises the internal volume of the first receptacle and/or the second receptacle which is maximum ca. 100 mL, maximum ca. 50 ml_, maximum ca. 10 ml_, maximum ca. 1 mL, maximum ca. 100 μl_, or maximum ca. 10 μL.
In a further embodiment, a receptacle of an apparatus according to the present invention may have a certain maximum volume. This is particular advantageous because conventional solid state screening during second manufacturing typically requires an amount of the solid material being in the order of kilograms, which is an amount that can be costly to obtain, especially for a newly developed active pharmaceutical ingredient (API).
In an embodiment, an apparatus according to the invention comprises the processing means arranged relative to the first and the second receptacle so as to subject the solid matter to two different kinds of simulations conditions.
In another embodiment, an apparatus according to the invention comprises the first receptacle arranged to house an internal optical monitoring probe.
In yet another embodiment, an apparatus according to the invention comprises the means for inducing crystallization comprising heating means in thermal contact with the first receptacle, and/or cooling means in thermal contact with the first receptacle.
It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention.
All patent and non-patent references cited in the present description are hereby incorporated by reference in their entirety. The invention will now be described in further details in the following non-limiting examples.
Figure 2 shows the Raman spectra collected from the wet massing and drying studies measured at the end points. Theophylline anhydrate was used as starting material in the wet massing experiment, while the monohydrate was exposed to drying.
Figure 3 shows the NIR spectra collected from the wet massing and drying studies measured at the end points. Theophylline anhydrate was used as starting material in the wet massing experiment, while the monohydrate was exposed to drying.
Figure 4 shows the various elements of the prototype used for expanded solid form screening. Left hand side: The 2x2 well-plate chassis with the inclusion of four vials. The primary unit is built out of aluminum while each vial is made out of stainless steel. Right hand side: Small scale processing equipment made out of stainless steel. Active heating/cooling of the vials can be performed using a circulating water bath (Ecoline RE106; Lauda Brinkmann, Westbury, NY) with attached thermostat (Ecoline ElOO; Lauda Brinkmann, Westbury, NY). The temperature of the primary well-plate unit can be monitored using a thermo sensor (ama-digit ad 15th, Germany) inserted into the center of the unit. The basic principle of the modular CryProc unit is that it can easily be expanded to the desired size.
Figure 5 shows Raman spectra collected from the milling and compaction studies. Amorphous nifedipine was used as starting material for both types of unit operations.
Figure 8 is a schematic diagram of an apparatus according to the present invention for solid state screening of a solid material SIM. The apparatus is arranged for inducing solid state transitions in the solid material by at least two different ways. First, the solid state transitions may be induced by crystallization of the solid material. The crystallization may be e.g. crystallization from a solution or a crystallization from a melt. Secondly, the solid state transitions may be induced by simulating secondary manufacturing of the solid material SM. The solid state screening may, in particular, comprise monitoring of solid state transitions i.e. phase or structural changes.
The apparatus comprises a first receptacle 10 for receiving the solid material SM. The receptacle 10 can be detachably mounted on the base part 20 or it can form an integral part of the base part 20. The base part 20 comprises means for inducing crystallization in the solid material SM in the first receptacle 10 i.e. the means for inducing crystallization may comprise heating means in thermal contact with the first receptacle 10, and/or cooling means in thermal contact with the first receptacle 10 as will be explained in more detail below in connection with Figures 9 and 10. A second receptacle 11 is also schematically indicated in Figure 8. As it will be appreciated, once the general principle of the present invention has been acknowledged, the teaching of the present invention can be extended to two, three, four etc. receptacles arranged on a common base part 20. Such a plurality or array of receptacles can be particular advantageous for high-throughput testing and development of one or more different kind of solid material SM, and/or with one or more processing conditions simulating secondary manufacturing.
The apparatus also comprises processing means 15 arranged relative to the first receptacle 10 for simulating secondary manufacturing conditions on the solid matter SM. The processing means 15 may be simulating any kind of processing during secondary manufacturing i.e. unit operations, or parts thereof, like size reduction, wet granulation, dry granulation, direct compression, melt granulation, spray drying, freeze drying, tabletting, and capsule filling. For merely illustrative purposes the processing means 15 has been drawn in Figure 8 as a mechanical processing means i.e. a compaction device such as a compression punch or die.
The simulated secondary manufacturing refers in this context to secondary manufacturing process steps carried out on a smaller scale than actual pilot or manufacturing scale. The first receptacle 10 may be arranged to house an internal optical monitoring probe (not shown in Figure 8), e.g. Raman or NIR can be performed via an optical fibre/probe connected to the receptacle 10. The monitoring or measurements can however also be performed outside the receptacle 10. Figure 9 is an exploded cross-sectional view of an apparatus according to the present invention showing two different kind of mechanical processing means i.e. a compaction device such as a compression punch or die 15a and wet massing device 15b. For clarity reasons the top section of the wet massing device 15b is not shown in this Figure, The processing means 15a and 15b are adapted to be received in the first 10 and the second 11 receptacle, respectively. Components for punching the die 15a and combined pressing and rotating of the wet massing device 15b, respectively, are not shown for clarity in the Figure, but standard components like power drills and compaction or compression devices can be utilised for that purpose.
The base part 20 comprises cooling means i.e. cooling ribs 21 and heating/cooling means i.e. conduction means 22 for flowing fluid, e.g. water, through the base part 20.
Figure 10 shows a top view of the base part 20 shown in Figure 9, the base part
20 being suitable for implementing the present invention. The base part 20 functions from a thermal point of view essentially as a heat sink with cooling ribs
21 (not visible in this top view) and heating fluid flowing through the pipes 22. The heat capacity of the base part 20 should therefore be substantially larger than the combined heat capacity of receptacle and the one or more receptacles 10, 11, 12 and 13. The dimensions of the base part 20 should accordingly be proportionated relative to the one or more receptacles 10, 11, 12, and 13. The internal volume of the first receptacle 10 and the second receptacle 11 may be maximum ca. 100 ml_, preferably maximum ca. 50 ml_, or most preferably maximum ca. 10 ml_. With a 5 ml_ volume and four receptacles as shown in Figure 12, the base part can be made in stainless steel (SS), or other suitable heat conduction material, with a cooling rib frame having outer dimensions ca. 27 x 95x 140 mm, cf. Figure 9, and a top portion of the base part 20 having outer dimensions ca. 30 x 70 x 70 mm, cf. Figure 9. Thermal monitoring can be performed by one or more thermal probes (not shown in Figure 10) integrated in or on the base part 20.
Figure 11 shows three different mechanical processing means 15a, 15b, and 15c for performing unit operations that simulate second manufacturing conditions, the means are seen from both a side view (top) and an end view (bottom). The compaction device (the compression punch) 15a is shown without a rear piece for making the mechanical connection to the punch actuator. The wet massing device 15b is similarly shown without the closing top section. The ball miller 15c comprises seven spherical protrusions as seen in the end view but any number of protrusions can be used.
Figure 12 shows a photograph of an apparatus according to the present invention. The annotation is the same as for Figures 8 - 11, i.e. the apparatus comprises three mechanical processing means; a compaction device (compression punch) 15a, a wet massing device 15b, and a ball-miller 15c, each mechanical processing means being received in the corresponding receptacles 12, 10, and 11, respectively. The fourth receptacle 13 is used for reference measurements.
Example 1
Crystallization and wet massing of theophylline anhydrate Table 1: List of ingredients
1 Theophylline anhydrate (BASF, Ludwigshafen, Germany)
2 Water (distilled) 3 Acetonitrile, analytical grade (VWR International, Rødovre, Denmark)
4 Acetic acid, analytical grade (J.T. Baker, Deventer, Holland)
5 Methanol, analytical grade (VWR International, Rødovre, Denmark)
6 Theophylline monohydrate (Unikem, København, Denmark)
The solid-state of theophylline (anhydrate and monohydrate) was verified by Raman spectroscopy (see below) using the reference spectra provided by Jørgensen et al. (Hydrate formation during wet granulation studied by spectroscopic methods and multivariate analysis. Pharm Res 2002, 19: 1285- 1291).
Crystallizations
A suitable amount of 1) was transferred to each of the four vials. 2.50 ml of each solvent, 2)-5), was separately added to a vial. The slurries were then heated to approx. 600C followed by cooling to ambient temperature. Heating/cooling of the device was done using a circulating water bath (Ecoline RE106; Lauda Brinkmann, Westbury, NY) and attached thermostat (Ecoline ElOO; Lauda Brinkmann, Westbury, NY). Solvents 3)-5) were evaporated after cooling whereas solvent 2) was removed by filtering. The solid-state of the recrystallized yield from each of the four vials was investigated by Raman spectroscopy (5 cm-1 resolution; Control Development, Inc., South Bend, IN) with a fiber optic probe (laser spot size 90 μm, focal length 5 mm; InPhotonics, Norwood, MA) and a diode laser (wavelength 785 nm; Starbright 785 S, Torsana Laser Technologies, Denmark) and a thermoelectrically cooled 2DMPP charge coupled device (CCD) (1024 x 64) detector (Control Development, Inc., South Bend, IN, USA). Yield recrystallized from solvents 3)-5) was analyzed using the average of 8 consecutive scans with a 4 seconds integration time, whereas the average of 4 scans and 1 second integration time were used for material from solvent 2). The use of fiber optics made it possible to measure directly in the vial. Samples were rotated during measurements to increase the effective sampling volume. All spectra were normalized, smoothed (by 9 point running mean) and corrected by standard normal variate (SNV), the latter to correct for baseline shift and tilt.
From Figure 1 it is seen that Raman spectra of recrystallized yield from solvents 3)-5) are similar to reference spectrum of TF anhydrate (the starting material). In contrast, the Raman spectrum of recrystallized yield from 2) is identical to spectrum of TF monohydrate reference (solid-state of reference material was verified with X-ray Powder Diffractometry (XRPD)). This indicates that a phase change, i.e. a solid-state transition, of TF anhydrate has occured in 1 out of 4 vials. Hence, polymorph or solid form screening of pharmaceuticals by crystallization from solution can be carried out using the device, "CryProc".
Wet massing
A suitable amount of 1) was transferred to a single vial. The solid state of the starting material was verified by Raman (see above) and near-infrared (NIR) spectroscopy (Control Development Inc., South Bend, IN) with a fiber optic probe, a tungsten light source and a thermoelectrically cooled InGaAs diode array detector. Each NIR spectrum was the average of 32 scans with a 10 milliseconds integration time. The wet massing device was attached to a power drill (Type SB.25, Holstebro Jernstøberi & Maskinfabrik, Denmark) and stirring of 1) was commenced at 1290 RPM. Immediately thereafter and during stirring, approx. 50 μl of 2) was added. Wet massing time was 2 minutes. The existence of granules was visually observed. Raman and NIR results shown in Figures 2 and 3, respectively, indicate the transformation of theophylline monohydrate as a result of the wet massing operation.
Drying
A suitable amount of theophylline monohydrate crystals produced from 1) was transferred to a vial and kept at 600C for 50 min. The solid-state of the starting material (i.e. prior to drying) was verified be Raman and NIR spectroscopy. The temperature in the center of the prototype unit was continuously monitored and kept at 60.50C. The solid-state was monitored every 30 seconds using Raman and NIR spectroscopy (see above) until reaching the end point after 50 min. Raman and NIR data at the end-point are presented in Figure 2 and 3, respectively. The spectra confirm the transformation of the monohydrate form into the anhydrate form, verifying that theophylline monohydrate is physically unstable towards heat.
Example 2
Milling and compaction of nifedipine Table 2: Ingredient list
1 Nifedipine (α form; stable), (Hawkins Pharmaceutical Group, MN, USA)
The solid-state of nifedipine was verified by Raman spectroscopy (see below) using the reference spectra provided by Chan et al. (Polymorphism and devitrification of nifedipine under controlled humidity: a combined FT-Raman, IR and Raman microscopic investigation. J Raman Spectrosc. 2004, 35:353-359).
Milling
The stability of amorphous nifedipine towards ball milling was investigated. Amorphous nifedipine was prepared by melting 1) at approximately 185°C and then quenching the melt on the ice. 30 mg of amorphous nifedipine was transferred to a single vial. Three balls (see Figure 4), corresponding to a ball to mass ratio of 50: 1, were added to the vial and the vial was sealed shut with a lid. Small-scale milling was simulated by shaking the vial on a vortex mixer at approximately 2500 shakes min-1 (speed 4.5). Milling was performed at room temperature (19 ± I0C), and no significant temperature increase was detected at the end of the milling (20 minutes). A very small amount of sample (approximately 1 mg) was taken for Raman analysis at several predetermined time intervals during the milling. All experiments of nifedipine were carried out in the dark, and no chemical degradation of nifedipine was observed after milling. The Raman system consisted of a Renishaw Ramascope System 1000 with a NIR diode laser (λ = 785 nm). The sample was placed on a microscopy slide, and viewed under an optical Raman microscope through a 5Ox objective (spot size of approximately 8x39 μm). A Rencam Charge Coupled Device (CCD) silicon detector was used to acquire Raman shifts. The exposure time for data collection was set at 10 s. and 2 accumulations per sample with a laser power of 100 mW. Wire V.2.0 software was used for instrument control and data acquisition.
From Figure 5 it is seen that amorphous nifedipine is transformed in the metastable β form after approximately four minutes of milling. Upon continued milling, there is a gradual conversion of metastable nifedipine into the stable α- form. Finally, after 20 minutes of milling the presence of α-nifedϊpine is more pronounced. Thus, small-scale ball-milling can induce phase (solid-state) changes, and thus be used as part of the combined strategy for effective solid form screening. Because the milling temperature was maintained at room temperature (19 ± I0C) in this study, not all the intermediate polymorphs of nifedipine were found.
Compaction The stability of amorphous nifedipine towards high pressures was investigated. A suitable amount of amorphous nifedipine was compressed directly in a single sample cup using the punch shown in Figure 6 and a manual hydraulic press (Perkin-Elmer, Germany). The applied pressure was approximately 100 MPa. The solid-state at the end point was confirmed by Raman spectroscopy. The result is shown in Figure 5. Compaction induced a phase change into the stable α form of 1) at the end point of the compaction operation.
As demonstrated in examples 1 and 2 above, based on the compounds theophylline and nifedipine, solid state changes are observed during all four simulated manufacturing steps: wet massing, drying, milling, and compaction. Example 3
Milling and compaction of sodium chloride crystals Table 3: Ingredient list 1 Sodium chloride, coarse (Brøste A/S, www.broste.com, Denmark)
Milling
A suitable amount of 1) was added to a vial. Triplicate NIR spectra (see above) were recorded to establish the spectral baseline of non-milled material (see Figure 3). In addition, particle size and shape was investigated by Scanning Electron
Microscopy (SEM, JSM 5200, Jeol, Japan) using 35 times magnification (see Figure 9). The sample was milled at 105 rpm for approx. 15 seconds using CryProc's milling device coupled to a power driller (Type UBM 30, Modigs Mekaniska Verkstad, Sweden). Milling is generally known to induce phase changes. The milled material was investigated by NIR and SEM. SEM micrographs shown in Figure 7 confirm a marked reduction in particle size and thus successful milling. Furthermore, a clear tilt of the NIR baseline is observed for the milled sample, indicating a change in the amount of specular reflectance when going from starting to milled material. This corroborates that the initial physical features of 1) have been changed as a result of the milling operation (i.e. particle size reduction).
Compaction
Milled material (see above) was compacted directly in a single sample cup using the punch designed for CryProc and a manual hydraulic press (Perkin-Elmer,
Germany). Applied pressure was approx. 100 MPa. Sample height was reduced by approx 1.6 mm as a result of the compaction step and a compact was formed. Compaction is generally known to induce phase changes.

Claims

Claims
1. Method for solid state screening by simulating secondary manufacturing of at least one solid material; wherein said solid state screening combines small scale crystallization in a receptacle and the evaluation of induced solid state changes in said receptacle, allowing crystallization and simulated secondary manufacturing to be performed simultaneously or consecutively; and wherein said secondary manufacturing comprises applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material.
2. Method according to claim 1, comprising the steps of: a. Providing a liquid in a receptacle, said liquid comprising at least one API or excipient. b. Crystallization by allowing said at least one API or excipient to solidify, for example by precipitation or congealing, forming said at least one solid material. c. Simulating secondary manufacturing by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material in said receptacle, d. Screening by measurement of the crystalline state of said at least one solid state material.
3. Method according to claim 1 or 2, wherein said secondary manufacturing is simulated by a compaction step.
4. Method according to any of the preceding claims, wherein said secondary manufacturing is simulated by a milling step, preferably before a subsequent compaction step.
5. Method according to any of the preceding claims, wherein said secondary manufacturing is simulated by a wet massing step followed by a drying step, preferably before a subsequent compaction step.
6. Method according to claim 5, wherein said wet massing step followed by said drying step, is followed by a subsequent milling step.
7. Method according to claim 5, wherein a milling step is followed by said wet massing step.
8. Method according to any of the preceding claims, wherein said secondary manufacturing is simulated in a step a) by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material.
9. Method according to claim 8, wherein said secondary manufacturing is further simulated in a step b) by applying at least one of the conditions of heating, cooling, pressure, strain, stress, shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material, subsequent to said step a), wherein said step b) is different from said step a).
10. Method according to any of the preceding claims, wherein said secondary manufacturing is further simulated in a number of steps by applying at least one of the conditions of heating, cooling, pressure, strain, stress and/or shear forces, solvent exposure and/or allowing a gas stream to pass over or through said at least one solid material, wherein each step is different from the previous step.
11. Method according to any of the preceding claims, wherein said secondary manufacturing simulates at least one of blending, wetting, wet massing, drying, granulation, milling, compaction, compression, tableting, coating, spray drying and freeze drying.
12. Method according to claim 11, wherein said milling is simulated by introducing mechanical stress in order to reduce particle size of the solid material.
13. Method according to claim 11, wherein said wet massing is simulated by adding a liquid to said at least one solid material followed by applying shear forces by contacting said at least one solid material and said liquid to a rotating, uneven surface.
14. Method according to claim 11, wherein said tableting is simulated by applying pressure to the solid material in order to reduce the volume of the solid material.
15. Method according to any of the preceding claims, wherein said at least one solid material is subjected to the conditions of said simulated second manufacturing in an amount of less than a value selected among 100 g, 50 g, 20 g, 10 g, 5 g, 2 g, 1 g, 500 mg, 300 mg, 200 mg, 100 mg, 50 mg, 25 mg, 10 mg, 5 mg, 2 mg, 1 mg, 500 μg, 300 μg, 200 μg, 100 μg, 50 μg, 25 μg, 10 μg, 5 μg, 2 μg, and 1 μg, preferably less than 3 g, in a chamber or receptacle.
16. Method according to any of the preceding claims, wherein said at least one solid material is selected among an API, an excipient or a composition.
17. Method according to any of the preceding claims, wherein said at least one solid material is an API for oral, dermal, topical, respiratory, intravenous, intraperitoneal, rectal, vaginal, ocular, nasal or buccal administration.
18. Method according to any of the preceding claims, wherein said at least one solid material is solubilised in an aqueous medium before crystallization.
19. Method according to any of the preceding claims, wherein said solid state screening comprises comparing at least two different solid forms, such as crystal forms, of said at least one solid material selected among a co- crystal, a solvate, or a derivative, such as a salt or an ester.
20. Method according to any of the preceding claims, for high-throughput solid state screening, wherein multiple samples of said at least one solid material are subjected to varying degrees of simulated secondary manufacturing processes and experimental results are gathered in a computer.
21. Method according to any of the preceding claims, for high-throughput solid state screening, wherein multiple samples of different solid materials are subjected to at least one simulated secondary manufacturing process and the measurement results are gathered, processed and organized in a computer.
22. Method according to any of the preceding claims, wherein the number of samples of said at least one solid material subjected to at least one simulated secondary manufacturing process is at least 2, 4, 6, 8, 10, 16,
32, 64, 128, 256, 512 or 1024.
23. Method according to any of the preceding claims, wherein said at least one solid material is subjected to at least a number of simulated secondary manufacturing conditions selected among 2, 4, 6, 8, 10, 16, 32, 64, 128,
256, 512 and 1024; whereby a number of unit operations selected among 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 are simulated.
24. Method according to any of the preceding claims, wherein solid state changes of said at least one solid material is identified by at least one of infrared (IR) spectroscopy, near-infrared (NIR) spectroscopy, Raman spectroscopy, terahertz pulsed spectroscopy (TPS), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), microcalorimetry, solution calorimetry, X-ray powder diffractometry (XRPD), Single crystal X- ray diffractometry (XRD), optical microscopy, Scanning Electron Microscopy
(SEM), solvent sorption/desorption analysis, and solid state NMR.
25. Method for examining solid state changes induced by simulated secondary manufacturing wherein small-scale samples, according to claim 15, are subjected to at least one of the simulated processes of claim 11, and the solid state changes are measured according to claim 24.
26.An apparatus for solid state screening of a solid material, the apparatus being arranged for inducing phase or solid state changes, said phase or solid state changes being induced by crystallization of the solid material and by simulating secondary manufacturing of the solid material, the apparatus comprising: a) a first receptacle for receiving the solid matter, b) means for inducing crystallization in the said solid matter in the first receptacle, and c) processing means arranged relative to the first receptacle for simulating secondary manufacturing conditions on the said solid material.
27. The apparatus according to claim 26, wherein the processing means are arranged for performing a unit operation, or parts thereof, comprising at least one of size reduction, wet granulation, dry granulation, direct compression, melt granulation, spray drying, freeze drying, tableting, and capsule filling.
28. The apparatus according to claim 26, wherein the processing means comprises mechanical processing means capable of simulating mechanical stresses during secondary manufacturing of the solid material in a drug formulation.
29. The apparatus according to claim 28, wherein the said mechanical processing means are capable of subjecting a main portion of the solid material in the first receptacle to said mechanical stresses substantially simultaneous.
30. The apparatus according to claim 29, wherein the main portion of the solid material constitutes at least 60%, preferably at least 70%, more preferably at least 80%, or most preferably at least 90% of the solid material receivable in the first receptacle.
31. The apparatus according to any of claims 26 - 30, wherein the processing means comprises a miller, such as a ball miller, receivable in the first receptacle.
32. The apparatus according to any of claims 26 - 29, wherein the processing means comprises a compaction device, such as a compression punch, receivable in the first receptacle.
33. The apparatus according to any of claims 26 - 29, wherein the processing means comprises a wet massing device receivable in the first receptacle.
34. The apparatus according to any of claims 26 - 33 further comprising a second receptacle for receiving the solid material, the means for inducing crystallization in the solid matter being in thermal contact with the second receptacle, and further processing means being arranged relative to the second receptacle for simulating secondary manufacturing conditions on the solid material.
35. The apparatus according to claim 26 or claim 34, wherein the internal volume of the first receptacle and/or the second receptacle is maximum ca. 100 mL, maximum ca. 50 ml_, maximum ca. 10 ml_, maximum ca. 1 mL, maximum ca. 100 μl_, or maximum ca. 10 μl_.
36. The apparatus according to claim 34, wherein the processing means is arranged relative to the first and the second receptacle so as to subject the solid matter to two different kinds of simulations conditions.
37. The apparatus according to any of the claims 26 - 36, wherein the first receptacle is arranged to house an internal optical monitoring probe.
38. The apparatus according to any of the claims 26 - 37, wherein the means for inducing crystallization comprises heating means in thermal contact with the first receptacle, and/or cooling means in thermal contact with the first receptacle.
PCT/DK2008/000394 2007-11-08 2008-11-07 Small scale solid state screening WO2009059605A1 (en)

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