Amorphous drugs and drug delivery systems

Transcription

1 Amorphous drugs and drug delivery systems Thomas Rades Faculty of Health and Medical Sciences Department of Pharmacy University of Copenhagen Universitetsparken København Ø DENMARK Dias 1

2 Outline Introduction: Solid dosage forms. Stability of amorphous materials. The preparation method for amorphous materials matters. Stable glass solutions can be prepared if one stays below the solubility limit of the drug in the polymer. Dissolution behaviour of amorphous glass solutions. Small molecules can also be used to make co-amorphous systems. These can be other drugs or amino acids. Amorphous forms of drugs may be prepared or may appear in situ.

3 Introduction The oral administration route is most desirable administration route Most convenient Safest Marketed Drugs Least expensive 50% Oral 50% Other Approx. 50% of all drugs are given orally

4 Preformulation Characterisation of drug Biopharmaceutics absorption: Biopharmaceutical Classification System Classification System (BCS) Permeability Class II Poor solubility Good permeability Class IV Poor solubility Poor permeability Class I Good solubility Good permeability Class III Good solubility Poor permeability Solubility 5 A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a ph range of 1 to 7.5. A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% /19/03

5 The Biopharmaceutics Classification System Marketed Drugs in Development drugs

6 Market Total US spending on pharmaceuticals in 2012: USD 325 Billion Market share of poorly soluble actives in 2002: USD 110 billion Market is expected to increase More poorly soluble drugs are introduced to the market Increasing market in developing countries

7 Poorly water-soluble drugs HYDROPHOBIC LIPOPHILIC BCS II, IV brickdust greaseballs Physico-chemical properties determine formulation approach

8 Prodrugs Salt formation Co-solvents Fast Track Drug Delivery and Targeting, Y. Perrie, T. Rades, 2012, 2 nd Edition Molecular level Cyclodextrins SEDDS SMEDDS Strategies to to improve solubility Particulate level Colloidal level Microemulsions Emulsions Lipid solutions Metastable polymorphs Amorphous systems Particle size reduction

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11 Prodrugs Salt formation Co-solvents Fast Track Drug Delivery and Targeting, Y. Perrie, T. Rades, 2012, 2 nd Edition Molecular level Cyclodextrins SEDDS SMEDDS Strategies to to improve solubility Particulate level Colloidal level Microemulsions Emulsions Lipid solutions Metastable polymorphs Amorphous systems Particle size reduction

12 Crystalline compounds Solids with orientational and positional long-range order in three dimensions. Liquid crystalline compounds State of matter in which the molecules have long range orientational or positional order in some but not all dimensions. Melt / Amorphous compounds Solids with no orientational or positional long-range order.

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15 Crystalline to amorphous transformation Crystalline Drug Solid with orientational and positional long-range order in three dimensions. low solubility stable Amorphous Drug Solid with no orientational or positional long-range order. high solubility instable

16 Amorphous form melt super-cooled melt amorphous solid crystalline solid T k T g Temperature T m

17 When do solid-state transformations occur? Crystallisation Milling Blending Granulation Drying Tabletting Tablet coating Storage Administration Solvent Heat Shear-stress/ induced heat Solvent Shear-stress/ Heat Pressure/ induced heat Heat Solvent Heat Humidity Heat Solvent Agitation induced heat

18 Marketed Product Amorphous APIs Accolate (zafirlukast) Ceftin (cefuroxime axetil) Accupril (quinapril hydrochlorid) Viracept (nelfinavir mesylate) Amorphous solid dispersions Cesamet (nabilone PVP) Gris-PEG (griseofulvin PEG) Kaletra (lopinavir/ritonavir PVP/vinyl accetat copolymer ) Sporanox (itraconazole hypromellose) Intelence (etravirine hypromellose)

19 Takehome messages Stability of amorphous materials. The preparation method for amorphous materials matters. Stable glass solutions can be prepared if one stays below the solubility limit of the drug in the polymer. Dissolution behaviour of amorhpus glass solutions. Small molecules can also be used to make co-amorphous systems. These can be other drugs or amino acids. Amorphous forms of drugs may be prepared or may appear in situ.

20 Stability of amorphous substances

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25 Figure1 Amorphous forms - relaxation Liquid Supercooled liquid Enthalpy/volume Real glass a Equilibrium glass Crystal b c T K T a T f T g T m Temperature

26 0.5 Total heat flow [W/g] t = 16 h t = 12 h t = 8 h t = 5 h t = 2 h fresh Temperature [K] Relaxation endotherms and temperature evolution of the glass transition temperature for QC simvastatin.

27 Correlation of stability with the KWW relaxation time The extent of relaxation as a function of ageing time was calculated and is plotted. The evolution of H relax with ageing time for all drugs was plotted and ϕ was calculated.

28 step equation Age sample for different lengths of time Measure Hrelax (t, T) and cp for different times Calculate H (0,t) Calculate φ (extent of relaxation) for different annealing times Plot the different φ using non linear regression to get τ and β H (0, t) = Cp T g T φ t, T = 1 H relax t, T Cp T g (t, T) Cp(T g T) φ = exp[ t τ β ]

29 Extent of relaxation griseofulvin indomethacin nifedipine simvastatin troglitazone fenofibrate Ageing time [h] Extent of relaxation acetaminophen cefuroxime axetil lacidipine salsalate tolbutamide Ageing time [h]

30 Percentage amorphous content ( ) after 30 days of storage at T g - 20 ºC and a.) relaxation time τ(kww) and b) stretched relaxation time τ β ( ). Error bars for the relaxation time lie within the symbol.

31 Takehome messages Stability of amorphous materials. The preparation method for amorphous materials matters. Stable glass solutions can be prepared if one stays below the solubility limit of the drug in the polymer. Dissolution behaviour of amorhpus glass solutions. Small molecules can also be used to make co-amorphous systems. These can be other drugs or amino acids. Amorphous forms of drugs may be prepared or may appear in situ.

32 Amorphous indomethacin - Different preparation methods Diffractograms of freshly prepared amorphous form of indomethacin prepared by different preparative techniques.

33 Amorphous indomethacin - Different preparation methods Thermograms of freshly prepared amorphous form of indomethacin prepared by different preparative techniques.

34 Amorphous indomethacin - Different preparation methods (a) Raman spectra (b) Scores plot (c) Loadings plot of all freshly prepared amorphous samples.

35 Figure1 Amorphous forms - relaxation Liquid Supercooled liquid Enthalpy/volume Real glass a Equilibrium glass Crystal b c T K T a T f T g T m Temperature

36 Stability Effect of annealing on the KWW relaxation function of BM γ-form and CM γ-form. Correlation of KWW relaxation time with the experimentally determined stability (onset of crystallization) for differently prepared amorphous forms.

37 Effect of different cooling rates on the stability of amorphous indomethacin Time temperature transformation diagram, showing the minimum cooling rate to avoid crystallisation (R c ). T m is the melting temperature T g is the glasstransition temperature T n and t n are the temperature and time point at the locus, respectively

38 (a) Raman spectra of amorphous samples of indomethacin, prepared from melts cooled at various cooling rates and (b) the corresponding PCA scores plot TTT-diagram showing the minimum cooling rate required to obtain amorphous indomethacin (solid line)

39 Influence of cooling rate of indomethacin melts on the glass transition temperature of the resulting amorphous forms Onset time of crystallisation for amorphous samples of indomethacin prepared from melts cooled at various cooling rates and stored at T g 20 C

40 Cryo-milled indomethacin Intensity (a.u.) 420 min 345 min 195 min 120 min 90 min 60 min 45 min 30 min 15 min 0 min Diffraction angle ( o 2 )

41 PDF - Cryo-milled indomethacin G (r) (a.u.) 0 min 15 min 30 min 45 min 60 min 90 min t [1] (a.u.) 30 min 45 min 60 min 90 min 120 min 195 min 345 min 420 min 120 min 195 min 345 min 420 min o r (A) Time (min) Onset of crystallisation ( o C) min 30 min min min 90 min min 195 min min 420 min Onset of crystallisation (min) min 60min 90min 120min 420min Milling time (min) Milling time (min)

42 Takehome messages Stability of amorphous materials. The preparation method for amorphous materials matters. Stable glass solutions can be prepared if one stays below the solubility limit of the drug in the polymer. Dissolution behaviour of amorhpus glass solutions. Small molecules can also be used to make co-amorphous systems. These can be other drugs or amino acids. Amorphous forms of drugs may be prepared or may appear in situ.

43 Solid dispersions Solid dispersion Number of phases Physical state of phase(s) Eutectic mixture 2 C / C Solid solution 1 C Complex 1 A or C Glass solution 1 A Amorphous suspension 2 A / A or A / C Glass (amorphous) solutions are ideal for increasing dissolution Maximally reduced particle size (molecular) Amorphous drug Intimate presence of water-soluble excipient

44 Preparation of glasses and glass solutions Spray drying from solution Crystalline Amorphous Liquid to amorphous solid freezing-in of disorder: Spray drying Melt extrusion Super critical fluids Co-precipitation Crystalline solid to amorphous solid inducing disorder: Ball milling

45 Glass solution Molecularly dispersed drug in an amorphous polymer carrier: Challenges Thermodynamic unstable Phase separation and crystallization Objective Ensuring thermodynamic stability The drug has to be soluble in the polymer The drug load needs to be below the solubility 45

46 Determination of drug solubility in polymers Equlibrium saturated state is achieved from demixing of a supersaturated solution After equlibrium at a given annealing temperature above the Tc, a change in Tg is correlated to a given solubility according to the Gordon-Taylor equation X IMC K K T g(pvp) Tg X IMC T T X T T X g(pvp) g IMC g IMC g IMC C K C p PVP p IMC The Flory-Huggins model is then applied to extrapolate the solubility curve to room temperature H R m 1 1 ln Tm T a v 1 v v 2 IMC 1 PVP PVP v IMC IMC, vpvp 1 X IMC 1 X IMC ΔH m and T m are the enthalpy of fusion and melting temperature for the drug, R is the gas constant, T a is the annealing temperature, λ is the molar volume ratio of the polymer and drug, χ is the Flory-Huggins interaction parameter and v IMC and v PVP are the volume fractions of drug and polymer respectively IMC X IMC PVP v IMC

47 Obtain supersaturation Spray drying of a solution of drug and polymer in a volatile solvent Film casting of same solution on a hot teflon plate Ball milling for long enough to ensure crystalline drug is amorphized Hot melt extrusion Melt granulation

48 Equilibrium solubility of IMC (X IMC ) in PVP K12 as a function of annealing temperature (T a ). Green diamonds ball milling, red circles spray drying, and blue squares from film casting. The data previously reported by Mahieu et al. (2013) is presented as black crosses (x).

49 Comparison of the three methods Residual plot Film casting Spray drying Ball milling 49

50 Comparison of the three methods Ball milling Spray drying Film casting Mechanical forces Ordered crystalline state Solvent evaporation Disordered state (solution) Crystal lattice interruption Time-consuming (8 hours) Evaporation Instant (<1 second) Solid dispersion Solid dispersion 50

51 Comparison of the three methods Ball milling Spray drying Film casting Mechanical forces Solvent evaporation Raman microscopy Heterogenous mixture Homogenous mixture *Patterson et al.,

52 Summary Method Preparation time API usage Product stability Reproducibility Fit to Flory- Huggins Ball milling 8 h 1 g Weeks Good Bad Film casting < 1 h < 1 g Months Bad Good Spray drying 1 h > 1 g Months Good Good 52

53 Equilibrium solubility of IMC (X IMC ) in PVP of different molecular weight as a function of annealing temperature (T a ).

54 Materials Celecoxib (CCX) Low aqueous solubility Polyvinylpyrrolidone (PVP) Hydrophilic Very hygroscopic Polyvinyl acetate (PVA) Hydrophobic Anhygroscopic Polyvinylpyrrolidone/vinyl acetate (PVP/VA) copolymer compositions (70/30, 60/40, 50/50 and 30/70 w/w) Polyvinylpyrrolidone/vinyl acetate (PVP/VA) 54

55 Predicted solubility [w/w] Demonstration of the recrystallization method 25,0 45,0 65,0 85,0 105,0 125,0 145,0 165,0 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1 Temperature [ C] Example of a solubility curve (CCX:PVP/VA 60/40) - Extrapolation using The Flory-Huggins equation - Prediction interval from a statistical analysis 55

56 Results Liquid Monomer Solubility Approach Recrystallization Method 56

57 Results Liquid Monomer Solubility Approach Recrystallization Method 57

58 Results Liquid Monomer Solubility Approach Plateau Recrystallization Method 58

59 LMSA does not take physical differences between monomer and polymers into account Results in linearity and possible overestimation of drug solubility It is possible to obtain the same solubility with less VP in the copolymer chain Enhanced physical stability due to decreased water absorption 59

60 This study found the Liquid Monomer Solubility Approach may overestimate drug-polymer solubility since it does not take the physical differences between monomers and polymers into account The predicted solubilities from the Recrystallization Method indicated that the solubility reaches a plateau due to size differences between the drug and interacting monomer molecules (VP) Copolymers can theoretically be customized to fit any given drug with a ratio and sequence of monomers that provide the optimal drug-polymer solubility and physical stability. 60

61 Takehome messages Stability of amorphous materials. The preparation method for amorphous materials matters. Stable glass solutions can be prepared if one stays below the solubility limit of the drug in the polymer. Dissolution behaviour of amorhpus glass solutions. Small molecules can also be used to make co-amorphous systems. These can be other drugs or amino acids. Amorphous forms of drugs may be prepared or may appear in situ.

62 The spring and parachute effect Brouwers et al. J. Pharm. Sci. 2009, 98 (8),

63 The spring and parachute effect Amorphous drug with a polymer Amorphous drug Brouwers et al. J. Pharm. Sci. 2009, 98 (8),

64 The spring and parachute effect Amorphous drug with a polymer Amorphous drug Brouwers et al. J. Pharm. Sci. 2009, 98 (8),

65 Aims What is the influence of a copolymers composition on nonsink in vitro dissolution behavior of amorphous solid dispersions What is the influence of a copolymers composition on in vivo performance of amorphous solid dispersions in rats Is a simple non-sink in vitro dissolution method predictive of in vivo performance (in vitro in vivo correlation) 65

66 Materials Vinylpyrrolidone (VP) Vinyl acetate (VA) Celecoxib (CCX) Hydrophilic Hydrophobic Poorly water-soluble ~ 3 μg/ml High T g Low T g Weak acid pk a = 11.1 PVP/VA is a synthetic copolymer produced by random free-radical polymerization of VP and VA in different monomer ratios (30, 50, 60 and 70% VP) 66

67 Non-sink in vitro dissolution CCX-PVP/VA 50/50 CCX-PVP/VA 60/40 CCX-PVP/VA 70/30 CCX-PVP CCX-PVP/VA 30/70 CCX amorphous CCX crystalline CCX-PVA 67

68 Non-sink in vitro dissolution CCX-PVP/VA 50/50 CCX-PVP/VA 60/40 CCX-PVP/VA 70/30 CCX-PVP CCX-PVP/VA 30/70 CCX amorphous CCX crystalline CCX-PVA 68

69 Non-sink in vitro dissolution CCX-PVP/VA 50/50 CCX-PVP/VA 60/40 CCX-PVP/VA 70/30 CCX-PVP CCX-PVP/VA 30/70 CCX amorphous CCX crystalline CCX-PVA 69

70 In vivo performance in rats CCX-PVP/VA 60/40 CCX-PVP CCX-PVP/VA 50/50 CCX-PVP/VA 70/30 CCX amorphous CCX-PVP/VA 30/70 CCX crystalline CCX-PVA 70

71 In vivo performance in rats CCX-PVP/VA 60/40 CCX-PVP CCX-PVP/VA 50/50 CCX-PVP/VA 70/30 CCX amorphous CCX-PVP/VA 30/70 CCX crystalline CCX-PVA 71

72 In vivo performance in rats CCX-PVP/VA 60/40 CCX-PVP CCX-PVP/VA 50/50 CCX-PVP/VA 70/30 CCX amorphous CCX-PVP/VA 30/70 CCX crystalline CCX-PVA 72

73 In vivo In vitro correlation Expected of in vivo performance based on AUC 0-4h from non-sink in vitro dissolution: Amorphous CCX perform better than crystalline CCX CCX-PVP/VA 30/70 perform better than crystalline CCX Crystalline CCX perform equal or better than CCX-PVA Amorphous CCX perform equal to CCX-PVP/VA 30/70 CCX-PVP/VA 50/50, 60/40, 70/30 and CCX-PVP perform better than any of the other four formulations CCX-PVP/VA 50/50 perform better than CCX-PVP 73

74 Conclusions Increasing the hydrophilic VP content increased the dissolution rate of the amorphous solid dispersion ( spring effect ) Increasing the hydrophobic VA content increased the crystallization inhibition of the amorphous solid dispersion ( parachute effect ) Both in vitro and in vivo it seems that there was an optimal ratio between the dissolution rate enhancing (VP) and crystallization inhibiting (VA) monomers in the copolymer (around 50-60% VP) A correlation between in vitro AUC 0-4h and in vivo AUC 0-24h indicated that the non-sink in vitro dissolution method was predictive 74

75 Takehome messages Stability of amorphous materials. The preparation method for amorphous materials matters. Stable glass solutions can be prepared if one stays below the solubility limit of the drug in the polymer. Dissolution behaviour of amorhpus glass solutions. Small molecules can also be used to make co-amorphous systems. These can be other drugs or amino acids. Amorphous forms of drugs may be prepared or may appear in situ.

76 Drug Drug Combinations Naproxen Cimetidine H2-receptor antagonist BCS class II Non-steroidal anti-inflammatory drug (NSAID) Side effect: Gastro-intestinal disorders BCS class III Used in the treatment of gastrointestinal disorders similar dosing range for NAP&CIM

77 Individual APIs before and after milling - XRPD T g of quench-cooled NAP = C T g = C

78 DSC XRPD Co-milled APIs at different ratios XRPD & DSC All ratios result in X-ray amorphous mixtures No trace of crystallinity in DSC T g = C T g = C T g = C

79 Physical stability - XRPD 60-day storage at dry conditions Most stable Not the highest T g after preparation Still stable after 6 months

80 Intrinsic dissolution Compared to crystalline APIs coamorphous NAP-CIM shows 4-fold increase in IDR of NAP 2-fold increase in IDR of CIM Amorphous CIM alone shows no increase in IDR compared to crystalline CIM likely due to immediate crystallization upon dissolution Co-amorphous NAP-CIM stays amorphous upon dissolution offers synchronized release of the two drugs Not significantly different (95% conf. level)

81 Indomethacin - Naproxen C H 3 OH O O HO H 3 C N O H 3 C O Cl both BCS class II Preparation method: Quench cooling

82 Indomethacin - Naproxen DSC homogeneous mixtures

83 Indomethacin - Naproxen Experimental vs. Gordon Taylor Excess component

84 Indomethacin - Naproxen DSC and Gordon-Taylor equation

85 Indomethacin - Naproxen

86 XRPD: Stability Day 21 NAP NAP IND

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88 Physical Stability of quench cooled IND-NAP Influence of NAP-IND ratio Beyer et al. 2015, (unpublished data).

89 Temparature Physical Stability of ball milled NAP-CIM Influence of NAP-CIM ratio 55 NAP:CIM 1:2 NAP:CIM 3:1 45 NAP:CIM 1:1 NAP:CIM 2: Tg 49.2 C 51.5 C 50.7 C 48.2 C Most stable Similar Tgs 5 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1 Weight fraction NAP

90 Drug Amino acids Aminoacids may interact on a molecular level with drugs From literature we know: HIS and ARG are able to form an amorphous phase upon freeze drying Interactions between aminoacids and drug molecules at their biological target site Use of receptor aminoacids as potential interactors?

91 BCS class II drug candidates with active site and aminoacids from active site Carbamazepine (Na-chanal; PHE, TRP) Indomethacin (COX2; ARG, TYR) Naproxen (COX2; ARG, TYR)

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93 Prepration of co-amorphous blends

94 Glass transition temperatures Sample content T g ( C) Sample content T g ( C) IND 36.7 ± 0.8 CBZqc* 56.1 ± 0.2 IND-ARG 64.1 ± 1.4 CBZ-TRP 81.0 ± 0.6 IND-PHE 47.8 ± 2.9 CBZ-PHE-TRP 75.1 ± 1.1 IND-TRP 68.7 ± 2.6 CBZ-ARG-TRP 65.4 ± 1.1 IND-PHE-TRP 63.1 ± 0.8 IND-ARG-PHE 77.9 ± 3.4

95 Physical stability study 40 C over 1 year CBZ, 7days CBZ-TRP CBZ-PHE-TRP CBZ-ARG-TRP IND-ARG-PHE IND-PHE-TRP IND-TRP IND-ARG IND-PHE, 6month IND, 7 days

96 Single component amorphization Indomethacin Tryptophan Furosemide Absorbance 0 min 5 min 15 min 30 min 45 min Absorbance 0 min 5 min 15 min 30 min 45 min Absorbance 0 min 5 min 15 min 30 min 45 min 60 min 60 min 60 min 90 min 90 min 90 min 3 hours 3 hours 3 hours Angle/2 ( ) Angle/2 ( ) Angle/2 ( ) Reference: Jensen et al (unpublished data).

97 Co-amorphization Indomethacin-tryptophan Furosemide-tryptophan 0 min 0 min 5 min 15 min 5 min 15 min 30 min 30 min Absorbance 45 min 60 min 90 min Absorbance 45 min 60 min 90 min crystalline furosemide crystalline indomethacin crystalline tryptophan crystalline tryptophan Angle/2 ( ) Angle/2 ( )

98 T g ( C ) DSC Glass transition temperature (T g ) Sample content Actual T g ( C) Theoretical T g ( C) Amorphous furosemide 78.6 ± Amorphous indomethacin 45.0 ± Amorphous tryptophan ± Co-amorphous furosemide-tryptophan ± Co-amorphous indomethacin-tryptophan 91.0 ± g l a s s t r a n s it io n t e m p e r a t u r e in d o m e th a c in -try p to p a h n fu ro s e m id e -try p to p a h n fu r o s e m id e in d o m e th a c in tr y p to p h a n M illin g t im e ( m in )

99 Supersaturation

100 Comparison to glass solutions?

101 Summary Drug - AAs Highly stable co-amorphous mixtures Improved dissolution Interactions possible Comparable with PVP solid dispersions Weight ratio between 1:0.5 and 1:1.5

102 Takehome messages Stability of amorphous materials. The preparation method for amorphous materials matters. Stable glass solutions can be prepared if one stays below the solubility limit of the drug in the polymer. Dissolution behaviour of amorhpus glass solutions. Small molecules can also be used to make co-amorphous systems. These can be other drugs or amino acids. Amorphous forms of drugs may be prepared or may appear in situ.

103 In situ amorphisation Molecular structures of indomethacin and Eudragit E

104 X-ray diffractograms of compacts of γ-imc Eudragit E physical mixtures at 3:1, 1:1 and 1:3 drug-to-polymer ratios, and the corresponding compacts after immersion at ph 6.8.

105 Glass transition temperatures of samples after immersion at ph 6.8 and IMC Eudragit E glass prepared by quench cooling In situ Quench cooled IMC ± 0.1 C IMC - Eudragit E 3: ± 1.0 C 61.9 ± 0.3 C IMC - Eudragit E 1: ± 0.2 C 57.4 ± 1.8 C IMC - Eudragit E 1: ± 0.9 C 49.1 ± 0.2 C Eudragit E 56.9 ± 0.5 C

106 Takehome messages Stability of amorphous materials. The preparation method for amorphous materials matters. Stable glass solutions can be prepared if one stays below the solubility limit of the drug in the polymer. Dissolution behaviour of amorhpus glass solutions. Small molecules can also be used to make co-amorphous systems. These can be other drugs or amino acids. Amorphous forms of drugs may be prepared or may appear in situ.

107 Thank you for your attention! Dias 107