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# Stability of Drug Preparations - PowerPoint PPT Presentation

Stability of Drug Preparations. Chapter 12. I. Introduction. A.Importance Stability is the guarantee of safety and effectiveness of any preparations B.Types of stability studies (1)chemical one: chemical degradation (2)physical one: physical appearance

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Stability of Drug Preparations

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Chapter 12

A.Importance

Stability is the guarantee of safety and effectiveness of any preparations

B.Types of stability studies

(2)physical one: physical appearance

(3)biological one: microorganism pollution

(4)stability of bioavailability: in vivo

A. Orders of reactions

-dC/dt=kCn

where -dC/dt is the rates of change for the reactants; k is the reaction rate constant; C is the concentration; n is the order of the reaction (n=0: zero-order; n=1: first-order; n=2: second-order…)

second-order

zero-order first-order a=b=c0 a≠b

Differential rate -dc/dt=k -dc/dt=kc -dc/dt=kc2 -dc/dt=kcacb

expression

Integrated rate k=(c0-c)/t k=(1/t)ln(c0/c) 1/c-1/c0=kt

expression

t1/2 c0/(2k) 0.693/k 1/(c0k)

t0.9 c0/(10k) 0.105/k 0.11/(c0k)

B. The Arrhenius equation Reactions

(1)showing the effect of temperature on the drug degradation rate

(2)integrated: k=Ae-Ea/RT

logarithmic: lgk=-Ea/(2.303RT)+lgA

rewritten as: ln(k1/k2)=(Ea/R)(1/T2-1/T1)

where Ea is activation energy (a constant and independent of temperature); 1 and 2 denote the two different temperature conditions; k is the constant of reaction rate; R is gas constant

(3)It is possible to conduct kinetic experiments at elevated temperature and obtain estimates of rate constants at lower temperatures by extrapolation of the Arrhenius plot (Accelerated stability testing)

III. Routes by which pharmaceuticals degrade temperature and obtain estimates of rate constants at lower temperatures by extrapolation of the Arrhenius plot (Accelerated stability testing)

(1)hydrolysis

(2)oxidation

(3)dehydration

(4)isomerization

(5)incompatibilities

(6)others: hydration, decarboxylation, pyrolysis

(1) temperature and obtain estimates of rate constants at lower temperatures by extrapolation of the Arrhenius plot (Accelerated stability testing)hydrolysis: esters (lactone) and amide (lactam)

methods for delayed hydrolysis:

controlling water content

controlling T

reduce the solubility of drugs

solid forms

(2) temperature and obtain estimates of rate constants at lower temperatures by extrapolation of the Arrhenius plot (Accelerated stability testing)oxidation: phenols, enols, unsaturated alcohol, arylamine

mechanism: reaction of free radical chains

induction: RH R• +H • (light, heat)

transmission: R • +O2 RO2 •

RO2 • +RH ROOH +R •

ROOH RO • + •OH (metal ion)

termination: RO2 • +x inactive product

RO2 • + RO2 • inactive product

methods for delayed oxidation: temperature and obtain estimates of rate constants at lower temperatures by extrapolation of the Arrhenius plot (Accelerated stability testing)

reduce oxygen content

reduce metal ion

lower T

avoid light

B. Physical degradation routes temperature and obtain estimates of rate constants at lower temperatures by extrapolation of the Arrhenius plot (Accelerated stability testing)

(1)vaporization

(2)aging

(4)physical instability in heterogeneous systems (suspensions, emulsions, creams and ointments)

A.pH—hydrolysis

(1)lgk versus pH profiles of different drugs

(specific acid-base catalysis)

1.0 reaction rate

F

HS

S－

0.5

0.0

2

3

4

5

6

pH

14 reaction rate

12

10

k,10-4s-1

8

6

4

5

6

7

8

9

10

11

pH

-3 reaction rate

25℃

-4

-5

-6

12

0

2

4

6

8

10

pH

-3.7 reaction rate

79.5℃

I＝0.5

-3.9

lgk,s-1

-4.1

-4.3

-4.5

12

0

2

4

6

8

10

pH

-3.5 reaction rate

80℃

-4.0

lgk,s-1

-4.5

-5.0

-5.5

12

6

7

8

9

10

11

pH

-3 reaction rate

60℃

-4

lgk,s-1

-5

-6

2

4

6

8

10

12

14

0

pH

-3.5 reaction rate

35℃

I＝0.5

-4.5

lgk,s-1

-5.5

-6.5

12

0

2

4

6

8

10

pH

-5 reaction rate

70℃

-6

lgk,s-1

-7

7

8

6

0

1

2

3

4

5

pH

-4.2 reaction rate

91.3℃

-4.4

lgk,s-1

-4.6

-4.8

0.5

0.7

0.9

1.1

1.3

1.5

1.7

1.9

pH

-2 reaction rate

25℃

-3

lgk,s-1

-4

-5

2

4

6

8

10

12

14

0

pH

(2) reaction ratemethod: the optimum pH for stability—pHm

calculating:pHm=1/2pKw-1/2lgkOH-/KH+

through testing: a series of solutions with different pH values—accelerated testing—lgk~pH profiles—pHm

(3)general acid-base catalysis

PBS, ABS

method: change the type or reduce the concentration

B. solvent—hydrolysis reaction rate

lgk=lgk∞-k’ZAZB/ε

where k is the reaction rate constant, k’is a constant, εis the dielectric constant，k∞ is the reaction rate constant when ε∞，ZA and ZB is the electric charge of the two ions of A and B, respectively

C. ion strength reaction rate

lgk=lgk0+1.02ZAZBI1/2

where k is the reaction rate constant, k0 is the reaction rate constant when I=0, ZA、ZB is the electric charge of two ions,respectively，I is the ion strength

D. Surfactants reaction rate

enhance or decrease the stability , determined by the results of testing

E. Other excipients

determined by the results of compatibility testing in order to choose correctly

F. Temperature reaction rate

In general, the higher T is, the faster the reaction rate is

Arrhenius equation

Avoid light during preparation and storage package is very important

H. Air (oxygen)—oxidation reaction rate

inert gas (N2, CO2)

vacuum-packed

reducing agents

synergists

(note: pH value range in which antioxidants are suitable to application)

p272

I. Metal ions—initiate oxidation reactions reaction rate

employ raw materials and excipients with higher purities

do not use metal instruments

use chelating agents (EDTA, citric acid, and tartaric acid)

J. Humidity (water)—major determinant of drug product in solid dosage forms

lower RH% during preparation

put drying agents in the package

K. Package materials reaction rate

glass, plastics, aluminum foil etc

“package evaluation”

A. Properties of stability of solid drug preparations

(2)be not uniform

(3)difference between exterior and interior

(4)multi-phase systems

(5)obtain a balance [Van’t Hoff equation: lnK=-ΔH/(RT)+α]

(6)effect of crystal form

(1)nucleation theory

(2)liquid-layer theory

(3)topochemical reactions

VI. preparationsStability testing in the pharmaceutical industry

A. Impact factor testing (Stress testing)

high T (60℃, 40 ℃)

high H (25 ℃, 75±5%, 90±5%) 10d

strong light (4500±500lx)

B. Accelerated testing preparations

done more frequently and for a shorter duration

(1)in general, three batches, with package, 40±2 ℃, RH75±5%, 6m(3m for clinical testing and 6m for production)

(2)specific preparations with various testing conditions

(3)obtain “tentative” expiry date (shelf time)

C. Long-term testing preparations

(1)in general, three batches, with package, 25±2 ℃, RH60±10%, 6m for clinical testing, 12m for production and go on

(2) specific preparations with various testing conditions

(3)obtain “definitive” expiry date

P279

F. Classical isothermal method--done in research dosage forms

(1)pre-testing to determine Ts and sampling time; determine analysis methods

(2)put samples at predetermined Ts, take a sample at predetermined times (t), and determine the drug concentrations

(3)obtain profiles of C ~t, and determine the reaction order (lgC~t: linearity, first-order)

(4)according to the equation: k=(1/t)ln(C0/C), obtain k at different Ts

(5)according to Arrhenius equation:

lgk=-Ea/(2.303RT)+lgA, obtain profiles of lgk~T

(6)calculate t0.9, k25 ℃, Ea , lgA

G. Stability testing in new medicine development dosage forms

(1)raw materials

(2)stability in formulation and preparation process study

(3)stability of package materials

(4)accelerated and long-term testing of preparations

(5)stability after marketing

(6)stability testing for any change in formulation, preparation process or package