solid state pharmaceutics

1. Solid State Pharmaceutics
Mr. Santosh S Sarnaik
MS Pharmaceutics
CEO of Only Pharmacy

2. levels of solid state pharmaceutics

3. Checkpoints in solid state pharmaceutics
• Excipient/additive compatibility
• Degration pathway and prediction analysis
• Wetting and hygroscopic property determination
• Mechanical properties(plasticity/elasticity)
• Particle size/shape and surface area characterization
• Solid state stability ( physical/chemical)

4. Solid state material
Amorphous
Crystalline
semicrystalline

5. Amorphous
• Disordered arrangement of molecule
• Rate of solidification > Rate of molecule alignment in 3D
• Size reduction, milling, compaction, solidification and drying
• Do not possess well defined M.P.
• Temperature below Tg ----glassy state and brittle
• Temperature above Tg-----rubbery
• Tg can be decrease by addition of plastisizer such as water,
DIDP, DINP, DEHP)

6. Polymorphs
• The substance with many shapes
• Polymorphism is the capability of any solid substance to occur in a
different types having different crystalline arrangement or
conformations
• Monotropic polymorphs- not stable at all temperature and pressure
e.g. glyceryl sterate, metolozone
• Enatiotrophic polymorphs- polymorph which change from one
polymorph to another by varying temperature and pressure
e.g. sulfur, carbamazepine, starch, sulindac, salmeterol,
acetazolamide

7. Pseudopolymorphism
• Solvates /hydrates
• Salts/co-crystals

8. Solvates/hydrates
• Solvent in crystal lattice of solid
• Water in crystal lattice of solid called hydrates
• Hydrates are of several types such as monohydrate, dihydrate,
trihydrate e.g. gliczide, glyburide, glimepiride, glipizide

9. Salts/ hydrates
• Low aqs soluble drugs
• Method of preparation- slow evaporation
• Co- crystal are forms which are solid at ambient temperature
when attached with ionic drugs lead to the formation of co-
crystals

10. Levels of solid state pharmaceutics
Molecular
level
Particle
level
Bulk
level

11. Molecular level
• Properties :- crystallinity, polymorphism,
solvated/amorphous/co-crystals forms
• Characterization:- microscopy, DSC, TGA, HSM, ssNMR,
FTIR, Raman, near IR, XRD, ssXRD

12. Particle level
• Properties :- crystal habbit, particle dimension, particle
morphology, effective surface area
• Characterization:- SEM, TEM, DSC, DLS

13. Bulk level
• Properties :- flow property, solubility, melting point, granulation
properties, tableting properties, compaction behaviour
• Characterization :- flow characterization

14. Bioavailability of solids
• MAD(Maximum Absorbable Dose)
• Lowest solubility of drug molecules to reach systemic circulation
• MAD can be determined by calculating the solubility S, at pH
6.5(small intestine pH), the intestinal absorption rate(Ka), the
small intestinal water volume(SIWV 250ml) and SITT
• 𝑀𝐴𝐷 = 𝑆
𝑚𝑔
𝑚𝑙
× 𝐾𝑎 min − × 𝑆𝐼𝑇𝑇(𝑚𝑖𝑛)
• 𝐾𝑎 𝑚𝑖𝑛 − = 𝑃
𝑐𝑚
𝑚𝑖𝑛−
×
𝑆𝑎𝑏𝑐 𝑐𝑚2
𝑆𝐼𝑊𝑉 𝑚

15. • In case where active diffusion is not performed:-
𝑃
𝑐𝑚
𝑚𝑖𝑛
= 𝐷
𝐶𝑚2
𝑚𝑖𝑛 −
×
𝑘
𝛿

16. Polymorphism and its types
Enantiotropics
Monotropics

17. Enantiotropy
• One polymorph is stable at particular temperature and pressure
and other at many.
• Tt should be determined

18. Monotropic
• Lower free energy
• Only form is stable
• Soluble at wide range of temperature and pressure

19. Density rule
• It was proposed that for non- hydrogenated system at absolute
zero, the maximally stable polymorphic form will have maximum
density due to high van- der waals forces
• Higher packaging (density)> lower free energy
• Hydrogen bond--- decreases the van der waal forces
• E.g. Acetaminophen and acetazolamide

20. Infra-red Rule
• The polymorph with a greator value of bond stretching is
considered as having a high level of entropy

21. Formulation method of polymorphs
Solvent evaporation
method
Slow cooling approach
Solvent diffusion
technique
Vapour diffusion method
Vaccum sublimation
method

22. Solvent evaporation method
• Add drug into solvent such as acetone, methanol, ethanol,
water, and dichloromethane.
• Evoporate solvent by rota evaporator
• Advantage- high purity and yield
• Disadvantage- desirability of recrystallization, small production
volume and expensive
• Example – famotidine

23. Slow cooling approach
• Less soluble drugs
• Firstly add solute in solvent and heat at temperature above boiling
point of solvent
• Saturated solution is formed which is then placed into stoppered
tube which is connected to dewar flask
• After several days it will lead to the formation of crystals
• Solvents- methanol, acetone, acetonitrile, ethyl acetate, and hexane
• Advantages- Large scale production and easy reproducible
• Disadvantages- low yield, higher input, chances of disordered or
twinned crystals
• Example- NaCl, CuSO4

24. Solvent diffusion technique
• Use when amount of drug is less, air sensitive and solvent
sensitive
• Solution is put into sample tube
• Solvent add by side to tube using pipette
• Crystallization of API is done
• Advantages- larger S.A., higher solubility and high
mechanical strength to crystals
• Disadvantages- low production yields and tedious solvent
selection
• Example- tolbutamide, pentacene

25. Vapour diffusion method
• Use when low qt of sample
• Advantages- less qt of sample for crystallization
• Disadvantages- time consuming, difficult solvent selection,
expensive and low yield
• Example- proteins

26. Vaccum sublimation method
• Desired when qt is less and the sample is thermolabile
• Advantages- excellent crystal variety
• Disadvantages- disordered or twinned crystals
• Example- Haloprogin

27. Crystallization
• Crystallization is a technique of forming atoms or crystals which
are further washed with solvents in which they are insoluble
but are miscible with the mother solvent

28. Classification of crystallization solvents
Dipolar aprotic- acetonitrile, DMSO,
Protic- water, methanol, acetic acid
Lewis acid- dichloromethane, chloroform
Lewis basic- acetone, ethyl acetate
Aromatic- toluene, xylene
Non- polar- hexane, heptanes, cyclohexane

29. Characterization of polymorphs
Thermal
analysis-
DSC, TGA
Spectroscopy-
Raman,
terahertz,
ssNMR
Powder XRD,
ssXRD
FT-IR
Zero order
models
CCDC Blind tests

30. Image 1: DSC

31. Image 2:- Raman spectroscopy

32. Image 3:-Powder XRD

33. Image 4 :- FT-IR

34. Evaluation techniques
Dissolution
Biological
studies

35. Dissolutions
• Phosphate buffer saline pH 7.4
• Time dependent solubility studies
• Dissoution pattern can be correlated with enthalpies of fusion
and m.p.
• Dissoution play an important role in determining which form of
polymorph will have higher solubility and eventually the
bioavailability

36. Temperature dependent solubility of
polymorphs:- Van’t Hoff plot
• Log molar solubility vs inverse of absolute temperature
•
∆𝐻
𝑅𝑇
+
∆𝑆
𝑅
• Where ∆𝑠 is dissolution entropy
• ∆𝐻 is dissolution enthalpy
• It is appropriate to anticipate good estimates for solvents where
the maximum solubility is resulting in a smaller van’t Hoff plot
curvature

37. Biological studies
• It can provide proper understanding about the biological fate
alterations owing to the physical form transitions
• Polymorphic studies are crucial as these forms play a vital role
in preclinical or clinical developments

38. Importance of solid state pharmaceutics

39. Introduction
• SSP significantly influences a variety of API’s properties
including flow ability, tableting, dissolution rate, solubility,
stability and even biological performance including efficacy and
toxicity
• SSP have a fundamental impact on two of the very important
factor that play a crucial role in the successful development of
the drug candidate which are solubility and stability

40. Importance of particle size
• Particles > 250 um – free flowing
• Particles < 100 um – poor flowing
• Paticles <10 um – cohesion ( resistant to flow)
• Particle shape ( spherical)
• Contact angle

41. Biopharmaceutical aspects of
particle size
• Nano size particles- pinocytosis
• Submicron particles- GLRT(M cells)
• 0.2% or less then dissolution is rate limiting step
• Micronization of griseofulvin- increase biological effect

42. Potential solid polymorphic forms
Crystals
Crystal solvate or hydrates
Crystal desolvated solvates
Crystal dehydrated hydrates
Amorphous

43. Formation of polymorphs : therotical
consideration
Conformational
polymorphism
Packing
polymorphism
Disppearing
polymorphism
ICH Q6A – polymorphism as a drug
substance

44. Conformational polymorphism
• When different conformer of same molecule occur in different
crystal forms the phenomenon is called as conformational
polymorphism
• Ocassionaly more than one conformer is present in the same
crystal structure
• Example- Ritonavir

45. Packing polymorphism
• The molecule share same molecular conformation but are
packed differently in 3D space of crystal lattice
• Example- form I and II of acetaminophen
• Dapaverine

46. Disppearing polymorphism
• It refers to a situation where the previous prepared crystal form
no longer appear after obtaining the more stable form
• Example- mannose picrate benzylidene-DL-piperitone,
benzocaine

47. Ostwald’s rule of stages
• According to this theory, one has to observe all metastable
forms before one finally observes the stable form
• Rate of nucleation is expressed as:
𝐽 = 𝐴𝑒𝑥𝑝(−16𝜋𝛾3
v2
/3k3
T3
(lns)2)
• Ostwald law of stages defines that the rate of nucleation of
metastable form is always higher than the stable form over all
temperature ranges
• On the other hand kinetic nucleation theory suggested that the
rate of nucleation of the metastable form is not higher over the
entire supersaturation range

48. Cross nucleation
• Cross nucleation occurs when a polymorph nucleates on the other
polymorph
• Cross nucleation have been observed for small organic molecules
as well as polymers from the melt or solution
• The polymorphic form having fastest growth rate will be eventually
observed regardless of the rate of nucleation
• Cross nucleation tends to occur when the free energy of two
polymorphs is equivalent and confirmed that the polymorph with the
fastest growth rate will appear in the end
• This also showed that common lattice plane between two cross
nucleated polymorphs at the interface are necessary

49. Additive induced polymorphs
selection
• Additive components can diminish the speed of nucleation
process by raising the critical supersaturation concentration
required for initiation of nucleation process and or interfacial
phenomenon
• Additive components can constructively associate with the
prenucli of the same specific forms of polymorphs or
enantiomers
• Additive components tends to attach to the rapidly budding face
of the stable polymorphs and prevents the growth of a stable
polymorphic form

50. Effect of polymorphism on
different drug properties
• Physical and thermodynamic properties
1. Morphology
2. Density and refractive index
3. Wettability
4. Melting point
5. Solubility
6. Thermal stability

51. • Kinetic properties
1. Dissolution
2. Kinetics of solid state reaction
3. Stability
• Surface properties
1. Surface free energy
2. Crystal habit
3. Surface area
4. Particle size distribution

52. • Mechanical properties
1. compressibility
2. Hardness
• Chemical properties
Reactivity

53. Characterization
of polymorphs
DSC TGA FT-IR
Raman
spectroscopy
Powder
XRD
ssXRD ssNMR
Terahertz
spectroscopy

54. Role of amorphous state in drug delivery

55. Introduction
• Amorphous material do not having sharp melting point like
crystalline materials
• When amorphous material cleaved….rough edges
• When crystalline material cleaved…….soft edges
• Amorphous material having more solubility and dissolution than
crystalline one
• Amorphous material having less physical and chemical
stability than the crystalline one

56. Glass transition temperature
• Tg is the temperature at which glassy state is converted into
rubbery state
• Tm is the temperature at which crystalline substance starts
melting
• Rapid cooling of melted crystalline substance may converted to
supercooled (rubbery state) liquid and upon further cooling this
supercooled liquid will converted to amorphous
• Amorphous will have higher enthalpy and specific volume

57. Thermodynamic necessity for Tg
• Entropy crisis is prevented by Tg
• Tk is the temperature at which configurational entropy of the
system reaches zero

58. The kinetic point of view of Tg
1. Free volume theory
Vo- volume occupied by its molecule
Vf- Free volume where fluid is free to move
Vc- critical value is obtained at Tg
2. Structural relaxation time
Tg coincide with the temperature at which mean relaxation time
(T) changes by two to three orders of magnitude

59. Factors affecting
Tg value
a. Structure related factors:
Increase Tm – increase Tg
Salt formation increases Tg more as compared to amorphous
b. Multicomponent system
Crystallization/degradation of one component may affect the
mixture’s Tg

60. c. Moisture
Decreases Tg
d. Preparation/measurement techniques-
• Different Tg for spray dried and freeze dried trehalose
• The value of Tg measured by DSC is dependant on the cooling
rate, usually a higher value is obtained by using a higher cooling
rate

61. Molecular
mobility
• Amorphous material <supercooled liquid amorphous>crystalline
• Glassy- thermodynamic less stable
• Rubber- thermodynamically more stable
A. Global mobility(α- relaxation)
Temperature above Tg increase
Below decreases
Crystallization tendency and physical stability depend on global
mobility

62. B. Local mobility:- (β- relaxation)
Attributed to movement of part of molecule such as side chains

63. Fragility of amorphous material
Above Tg- more viscosity
Angell’s classification: a) strong glass formers
b) fragile glass formers
a) Strong glass former(Tm/Tg>1.5)
• Minimal molecular mobility changes at Tg
• Activation energy is temperature independant
• E.g. protein

64. b) fragile glass formers ( Tm/Tg<1.5)
 Higher molecular mobility changes at Tg
 Activation energy is temperature dependant
 E.g. pharmaceutical amorphous substances

65. Physical stability of polymorphs
• Nucleation at lower temperature
• Crystal growth at higher temperature
• Storage Tg-50k to avoid crystallization

66. Chemical stability of polymorphs
A. Enhanced rate of degradation
• Amorphous cefotoxin sodium > crystalline
• Positional specificity crystalline material may lead to
degradation
• Different degradation pathways and reaction for the amorphous
and crystalline insulin respectively
B. Changes in mechanism and kinetics of degradation reaction
• Faster degradation shown by amorphous than crystalline

67. Shelf life prediction of amorphous
pharmaceutical preparations
• Accelerated stability studies  misleading results
• Vary at above and below Tg

68. Glass forming ability
• It is defined as relative ease of forming the amorphous state
during processing
• Material that exhibits Arrhenious pattern in Angell’s plot have
high glass forming ability

69. Significance of amorphous state
• New drug candidate having less aqs solubility, lower
dissolution rate is the challenge for making formulation
• Approaches to increase solubility are:
1. Salt formation
2. Particle size reduction
3. Complexation
4. Surfactants
5. Prodrug formation
6. Amorphisation

70. Solubility enhancement of API
• Amorphous material having higher free energy, more solvent
exposed surface area and higher molecular mobility due to
this it having more solubility and dissolution rate
• Following equation is used to predict the solubility of amorphous
form
∆𝐺𝑇𝑎𝑐
𝑇 = −𝑅𝑇 ln(
𝜎𝑎
𝑇
𝜎𝑐𝑇
)
• ∆𝐺𝑇𝑎𝑐
𝑇 is difference in free energy
• 𝜎𝑎 – amorphous
• 𝜎𝑐- crystalline

71. Spring
parachute effect
• Amorphous form recrystallize into the aqs. Media leads to
decrease solubility is called as spring parachute effect
• Higher solubility from one side and plasticization effect from
other side

72. Functionality enhancement of pharmaceutical
excipients
1. Tablet compression
2. Polymeric tablet coating
3. Antiplasticization approach
4. Drug- carrier/ polymer interaction
5. Nano- confinement in MSN
6. Amorphous solid dispersions
7. Inorganic mesoporous carriers

73. Tablet
compression
• Amorphous compound are viscoelastic
• Direct compression is possible in amorphous form
• It also depend upon water content. For example MCC exerts
optimum direct compression property at 4 to 6 % water content

74. Polymer
tablet coating
• Amorphous polymer coat will be less brittle and more
resistant to cracking and fracture

75. Techniques for stabilization of amorphous forms
in pharmaceutical formulations
1. Storage at lower temperature than Tg
2. Antiplasticization approach

76. Storage at lower temperature than Tg
• Store at temperature Tg-50k to prevent the crystallization
• But it is not always stabilization at this temperature due to
complex relation between Tg and physical stability

77. Antiplasticization
approach
A. During storage-
decrease Tg – decrease lower mobility – stabilization
B. Upon dissolution
Polymer stabilizes amorphous material via:-
Formation of hydrodynamic layer around and dissolved drug
molecule
By increasing viscocity of dissolution medium
Preventing precipitation of drug from supersaturated solution

78. Gorden-taylor equation to binary amorphous
mixtures
𝑇𝑔𝑚𝑖𝑥 = 𝜔1. 𝑇𝑔1 +
𝐾. 𝜔2. 𝑇𝑔2
𝜔1 + (𝐾. 𝜔2)

79. Simha- Boyer rule
• To indicate ideality of mixing of two components
• To assess the different levels of second material on Tg of
another to evaluate the degree of intermolecular interaction of
individual components and between the drug and the polymeric
carrier
𝐾 =
𝜌1 × 𝑇𝑔1
𝜌2 × 𝑇𝑔2

80. Assessment of the effect of different levels of a
second material on Tg of another
• Increase in water content decreases the Tg

81. Evaluation of the intermolecular interaction of individual
components and between the drug and polymeric carrier
• Positive deviation- drug carrier interaction is more than
intermolecular interaction
• Negative deviation- drug carrier interaction is less than
intermolecular interaction
• Good fit- good mixing without interaction

82. Drug- carrier/ polymer interaction
• Limiting molecular diffusivity of amorphous drug
• Stabilization of probucol amorphous form through hydrogen
bonding with PVP

83. Nano- confinement in MSN
• MSN having higher surface energy after loading of drug which
is amorphous into MSN it becomes lower free energy i.e. stable
form

84. Amorphous solid dispersions
• 1st generation- crystalline drug + crystalline carrier( sucrose,
sorbitol, mannitol)
• 2nd generation- amorphous solid dispersion in that we must
add >/= 50 % by weight (polymer)
• 3rd generation- use of surfactant like PEG, TPGS

85. Mechanism of
dissolution
enhancement
• Decrease particle size - -increase wettability – increase
solubility
• Supersaturated solution
• Increase drug dispersibility

86. Polymer used in
amorphous solid
dispersions
• Ability to stabilize drug in amorphous form
• e.g. MC, HPC, HPMC, HPMC phthalate , PVP

87. Inorganic
mesoporous carriers
• High drug loading
e.g. magnesium aluminometasilicate calcium silicate

88. Preparation of amorphous
solid dispersions
solvent based methods
Vaccum solvent evaporation
Spray drying and related methods
Freeze drying and related methods
Addition of antisolvent
Electrospray technique
Supercritical fluid based methods

89. Solvent free
methods
vapour condensation
Mechanical destruction of crystalline material
Rapid cooling of melt
Fusion method
Hot melt extrusions

90. Innovative
methods
• Melt extrusion

91. Characterization of
amorphous material
1. Thermal analysis- DSC, isothermal microcalorimetry
2. Spectroscopic techniques- XRD, vibrational spectroscopy,
ssNMR
3. Microscopic techniques – microthermal analysis
4. Vapour sorption
5. Gas/ liquid displacement pycnometry
6. Viscosity or viscoelastic characterization
7. Phosphorescent/ fluorescent molecular probes

92. References
• Maheshwari, R., Chourasiya, Y., Bandopadhyay, S., Katiyar, P. K.,
Sharma, P., Deb, P. K., & Tekade, R. K. (2018). Levels of Solid State
Properties. In Dosage Form Design Parameters (pp. 1–30). Elsevier.
https://doi.org/10.1016/b978-0-12-814421-3.00001-4
• Bhatia, A., Chopra, S., Nagpal, K., Deb, P. K., Tekade, M., & Tekade, R.
K. (2018). Polymorphism and its Implications in Pharmaceutical
Product Development. In Dosage Form Design Parameters (pp. 31–65).
Elsevier. https://doi.org/10.1016/b978-0-12-814421-3.00002-6
• Mansour, R. S. H., Deb, P. K., & Tekade, R. K. (2018). Role of
Amorphous State in Drug Delivery. In Dosage Form Design Parameters
(pp. 105–154). Elsevier. https://doi.org/10.1016/b978-0-12-814421-
3.00004-x

93. Thank You!