Impact of Moisture on Pharmaceutical Products and Processes

1
Impact of Moisture on Pharmaceutical Products and
Processes
2

• Educational Outcomes

• Identify selected process and product
  characteristics that are influenced by moisture
• Identify methods that can be used to determine
  moisture content and describe the positive and
  negative attributes of each method
• Describe relationships between relative humidity
  and moisture content for drugs and excipients

3

• Properties of Pharmaceutical Interest Influenced
  by Water

• Chemical Stability
• Crystal Structure
• Powder Flow
• Compaction
• Lubrication
• Dissolution Rate
• Polymer Film Permeability

4

• Water Vapor Sorption for Aspirin (120 days/25 deg
  C)

1.2
Tablets
1
Powder
0.8
Moisture Content
0.6
0.4
0.2
0
0
20
40
60
80
100
Relative Humidity
5

• Degradation of Aspirin
• at 100 RH and 25 deg C

1.2
1.0
0.8
Aspirin Powder
Moles SA/100 g Solid
0.6
0.4
0.2
Aspirin Tablets
0
20
40
60
80
100
120
time (days)
6

• Unit Operations that Depend on the Amount and
  State of Water

• Wet Granulation
• Extrusion
• Spheronization
• Tray Drying
• Spray Drying
• Freeze Drying
• Fluid-bed Drying
• Tableting
• Aqueous Film Coating

7

• DiPac Tablets
• Effect of Moisture Content on Compactability

200
4.58 MC
4.15 MC
160
3.52 MC
120
Hardness (N)
2.72 MC
80
2.34MC
40
0
20
40
60
80
100
Compression Pressure (MPa)
8

• Anhydrous Lactose Tablets
• Effect of Moisture Content on Compactability

10
0.33 MC
0.58 MC
8
2.05 MC
3.30 MC
6
5.13 MC
Hardness (Kg)
4
2
0
40
80
120
160
200
240
Pressure (MPa)
9

• Compaction of Microcrystalline Cellulose

170
5.1 MC
150
130
Hardness (N)
0.07 MC
110
90
70
50
100
120
140
160
180
200
220
Compression Force (kg)
10

• Experimental Tools

• Moisture Sorption
• Loss on Drying
• Karl Fisher Titration
• Thermal Gravimetric Analysis
• Differential Scanning Calorimetry
• Optical Microscopy

11

• Moisture in Pharmaceuticals Stages in Scientific
  and Regulatory History

• Amount of water in products of natural origin
• Issues of potency and commerce
• Water recognized as a determinant of the physical
  properties of drugs and dosage forms
• Introduction of the concept of "free" and "bound"
  moisture
• State of water is as important as the amount of
  water
• Even small amounts of "bound" moisture can have a
  dramatic impact

12

• An Investigational Dichotomy

Water Vapor Sorption
Characterization
Role of Moisture
Impact
Case Studies
13

• Characterization

Complete Thermodynamic Study
Enthalpy Determinations
Kinetics of Adsorption
Surface Area Measurement
Sorption Isotherms of Pure Components
Water Vapor Sorption
14

• Impact

Case Studies
Water Indictment
Experimental Design
Solution of the Problem
15

• Correlation of Product or Processing Problems
  with Moisture

Sorption Isotherms of Pure Components
Water Vapor Sorption
Role of Moisture
Case Studies
Water Indictment
16

• Questions

• Is water chemically bound to the solid or does it
  interact through weaker non-specific forces?
• Is the water present in a two-dimensional gaseous
  state or does it resemble a condensed liquid?
• Are water molecules localized in a specific site,
  in pores, or in inter-particulate spaces?

17

• Questions

• What is the effect of natural temperature
  fluctuations on all aspects of solid-water
  interaction?
• How easily is the water released (desorbed) once
  it has been adsorbed?
• Does the moisture content reflect that of an
  equilibrium state?
• How is the water distributed in a blend of solids
  with different affinities for moisture?

18

• Heterogeneous Moisture Distribution

Formulation
Hydrophobic drug (90)
Hydrophilic excipient (10)
Blend has a 2 Moisture Content.
Assuming all the water is associated with the
hydrophilic excipient, what will the moisture
content of this excipient be?
19

• USP/NF

• "Many Pharmacopeial articles either are hydrates
  or contain water in adsorbed form. As a result,
  the determination of water content is important
  in demonstrating compliance with Pharmacopeial
  standards."
• Compliance with official standards is intended to
  insure the reproducibility of a material from lot
  to lot and/or supplier to supplier.

20

• USP/NF

• Approximately 85 of the articles in the USP/NF
  do not have moisture specifications.
• Moisture specifications do not necessarily relate
  to the functionality of an excipient.

21

• Setting and Using Moisture Specifications

• Moisture content depends on the experimental
  method employed in its determination.
• How does knowledge of the moisture content of a
  drug or excipient influence decisions related to
  its use?

22

• Nonspecific Dehydration

Stress
Solid (x H2O) Solid (y H2O)
(x-y) H2Os
x initial moisture content of solid y
moisture content of solid after stress s state
of liberated water Conditions x gt y y 0 is
complete dehydration
23

• Moisture Content Determination
• Stresses used to produce dehydration

• High Temperature/Low Pressure
• Anhydrous Solvent Extraction

24

• Classical Methods for Moisture Content
  Determination

• Titrimetric Method
• Karl Fisher Titration
• Gravimetric
• Loss on Drying
• Thermal Gravimetric Analysis

25

• Karl Fisher Titration

• Specific for water
• Works best for materials that are soluble in the
  titration medium
• Water must diffuse out of insoluble solids
• Isothermal
• Newer systems offer a furnace accessory which can
  be used to drive off water into the titration
  medium

26

• Loss on Drying

• non specific
• high temperature and low pressure conditions
• alteration of sample

incomplete release of water
degradation of solid
27

• Chemically Bound Water
• Hypothetical Solid

• Anhydrous Molecular Weight 162
• Forms a monohydrate
• Solubility 50 W/W
• Critical transition humidity 60 RH

28

• Stepwise Sorption Isotherm

200
Colligative Behavior
160
Solution
120
Solubility
Moisture Content
80
Monohydrate Saturated Solution
Monohydrate
40
Anhydrous
Solid
0
0
20
40
60
80
100
Relative Humidity
29

• TGA of Dicalcium Phosphate Dihydrate

25
Region I
20
15
Moisture Content
10
Region II
5
0
25
275
150
(1.5 deg/min)
Temperature (deg C)
30

• Dehydration of Dicalcium Phosphate Dihydrate
  (milled)

Region I CaPO4 . 2H2O CaPO4. 11/2 H2O
1/2 H2O Region II CaPO4. 11/2 H2O
CaPO4 11/2 H2O
31

• Handbook of Pharmaceutical Excipients

• both dibasic calcium phosphate dihydrate and the
  anhydrous material are non-hygroscopic and absorb
  minimal amounts of water at up to approximately
  90 RH
• at temperatures greater than about 45 oC the
  dihydrate starts to lose its water of
  crystallization
• the anhydrous material (formed at temps gt 200 oC)
  can not be rehydrated to form the dihydrate

32

• DSC of Dicalcium Phosphate

1 mCal/sec
Anhydrous Dicalcium Phosphate with Adsorbed
Moisture
Dicalcium Phosphate Dihydrate
30
230
130
(20 deg/min)
Temperature (deg C)
equilibrated for 3 months at 25 deg C and 100 RH
33

• Normalized KF Titration of Dicalcium Phosphate

25
20
Dihydrate, Milled Form
Volume of KF Reagent (mL)
15
10
5
Dihydrate, Unmilled Form
0
12
24
36
48
60
time (min)
34

• Normalized KF Titration of Dicalcium Phosphate

25
20
Anhydrous Sample with Adsorbed Moisture
Volume of KF Reagent (mL)
15
10
Dihydrate, Milled Form
5
0
2
4
6
8
10
time (min)
35

• Dehydration of Selected Hydrates

120
CaSO4 . 2H2O CaSO4. 11/2 H2O
1/2 H2O CaSO4. 11/2 H2O CaSO4
11/2 H2O CuSO4 . 5H2O CuSO4.
3H2O 2H2O CuSO4 . 3H2O
CuSO4. H2O 2H2O CuSO4 . H2O
CuSO4 2H2O CaCl2 . 6H2O
CaCl2 . 4H2O 2H2O CaCl2 . 4H2O
CaCl2 . 2H2O 2H2O CaCl2 . 2H2O
CaCl2 . H2O H2O CaCl2 . H2O
CaCl2 H2O
170
30
110
250
200
36

• TGA of Lactose Monohydrate

6
5
4
Moisture Content
3
2
1
0
25
275
150
(1.5 deg /min)
Temperature (deg C)
37

• DSC of Lactose Samples

1 mCal/sec
Anhydrous Lactose with Adsorbed Moisture
Lactose Monohydrate
Anhydrous Lactose
30
230
130
(20 deg/min)
Temperature (deg C)
38

• Equilibrium Moisture Content of Anhydrous
  Lactose

2 weeks exposure in RH chamber at 21-25 deg C.
39

• Adsorption of Water by Microcrystalline Cellulose

25
6RH
20
11RH
18RH
25RH
15
31RH
Moisture Content
49RH
10
70RH
82RH
5
90RH
100RH
0
0
2
4
6
8
10
time (days)
40

• Moisture Sorption Isotherm for Microcrystalline
  Cellulose

25
20
Adsorption
Desorption
15
Moisture Content
10
5
0
0
20
40
60
80
100
Relative Humidity
41

• TGA of Microcrystalline Cellulose

4
3
Moisture Content
2
1
0
25
225
125
(1.5 deg /min)
Temperature (deg C)
42

• DSC for Microcrystalline Cellulose

1 mCal/sec
30
230
130
(20 deg/min)
Temperature (deg C)
43

• Normalized KF Titration of Microcrystalline
  Cellulose

25
20
15
10
5
0
12
24
36
48
60
time (min)
44

• Type II Isotherm with Hysteresis

25
20
Desorption
15
Moisture Content
D
10
A
B
5
Adsorption
C
0
0
20
40
60
80
100
Relative Humidity
45

• Sorption Isotherm for Directly Compressible
  Sucrose

Moisture Content
Desorption
Adsorption
Relative Humidity