Estabilidad y Inestabilidad de Los Medicamentos

Estabilidad
Tecnologia Farmacutica.
Estabilidad de Medicamentos

Contenido en sustancia activa
Caracteristicas esenciales de calidad:
Contenido en sustancia activa

Forma farmacutica y caracteres
organolpticos
Flora microbiana
Toxicidad
Biodisponibilidad

reduccin del 10% en sustancia activa

Toxicidad no aumenta debido a productos de
degradacin

Estabilidad
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Estabilidad
Estudios de estabilidad
Alteraciones de los medicamentos
Sobre la sustancia activa

Fase de preformulacin:

Slido y disolucin
Compatibilidad con excipientes
Estabilidad frente a operaciones bsicas

Fecha de caducidad: mes y ao

Periodo de validez mximo 5 aos (RD
736/1987 de 17 de marzo)
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Tecnologa Farmacutica
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Periodo de validez:
Estables, seguros, eficaces

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Estabilidad
Inestabilidad Fsica
Inestabilidad Qumica
Inestabilidad Microbiolgica
Especialidad terminada
Ensayos a largo plazo
Ensayos de envejecimiento acelerado.
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Estabilidad
Inestabilidad Fsica: alteracin de las

caracteristicas galnicas

Inestabilidad qumica
Consecuencias:
Aspecto
Regularidad de la dosificacin
Biodisponibilidad (caducidad biofarmacutica)

Cintica qumica
Orden y molecularidad de la reaccin
Vias degradacin fsica:
Polimorfismo
Crecimiento cristalino
Sedimentacin
Floculacin
Coalescencia
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Estabilidad
Estabilidad
Stability Calculations
D
a typical chemical reaction
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Estabilidad
Reaction rate [D]*[W]
D and W, "colliding" to form one or more product molecules,
the rate of reaction: proportional to the number of collisions a
the number of collisions is proportional to the product of the concentrations of the

two species:
we let k2 be the rate constant
Reaction rate [D]*[W]
Reaction rate corresponds to the rate of loss of D and is denoted (d[D]/dt)
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d[D]
[D][W]
dt
d[D]
= k 2 [D][W]
dt
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Estabilidad

Estabilidad
Order of reaction:
Order of reaction: sum of the exponents of

the concentration terms in the rate equation
d[D]
= k 2 [D][W]
dt
If the water concentration W is held constant (by having a

large excess, as in most solutions) then :
d[D]
= k 2 [D][W]
dt
d[D]
k1[D]
dt
where k1= k2 [W]
Second order reaction

and the reaction is apparent first order or pseudo first order
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Estabilidad
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Estabilidad

Order of reaction:
If, now, in addition, we also fix the drug
concentration (e.g., by making a suspension), the
equation becomes:
Orden
d[D]
= k0
dt
where k0 = k1[D] = k2[D][W]
C*t-1
-dC/dt=-k*C
t-1
-dC/dt=k*C2
-dC/dt=k*C*B
-dC/dt=k*Cn
C-1*t-1
and the reaction is apparent zero order
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Ecuacin
velocidad
-dC/dt=k
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Unidades k
Cn-1*t-1
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Estabilidad
Estabilidad
First-Order Calculations
D
0
1
-dC/dt=-k*C
-dC/dt=k*C2
[D] = [D]0 e k1t
Ecuacin
integrada
First order
C = C0 k t
C = C0 e
k t
1
1
=
+ k t
C C0
First order
1000.0
500.0
C o n c e n tra tio n
Ecuacin
velocidad
-dC/dt=k
L n C o n c e n tra tio n
Orden
400.0
100.0
300.0
200.0
10.0
100.0
1.0
0.0
100
200
300
400
500
100
200
300
400
500
Time (min)
Time (min)
T1/2
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Estabilidad
Estabilidad
The half-life, t:
is the time for [D] to become [D]/2,
The shelf-life, t90:
usually taken to be the time for [D] to reach 0.90[D], that is,
10% decomposition,
[D]0
= ln[D]0 k1t 12
2
ln 2
0.693
= t 12
t 12 =
k1
k1
ln
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t 90 =
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0.105
k1
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Estabilidad
Example:
aspirin (acetylsalicylic acid)
at pH 2.5 the (pseudo-first-order) rate constant is 5
x 10-7s-1 at 25C.
Zero-Order Calculations
rate equation with no concentration dependence.
[ D]
0.693
t 12 =
= 1.39 x 106 s
5 x 10-7
0.105
= 2.1 x 105 s
5 x 10-7
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[D] = [D]0 - k0*t
Half life
d[D] = k 0dt
0
[D] = [D]0 - k0*t
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Estabilidad
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Estabilidad

[ D]0
shelf life
t 90 =
d[D]
= k0
dt
Integrating from t = 0 to t = t with [D] = [D]0 at t = 0,
half-life
Estabilidad
D] = [D]0 - k0*t
Zero order
1000
900
800
Concentration
0.5[D]0
t 12 =
k0
Shelf-life
700
600
500
400
300
200
100
0.1[D]0
t 90 =
k0
0
0
20
40
t 12 =
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60
80
Time mins
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0.5[D]0
k0
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Estabilidad
Estabilidad
TEMPERATURE EFFECTS
Example: aspirin (acetylsalicylic acid)

at pH 2.5 the (pseudo-first-order) rate constant is
5 x 10-7s-1 at 25C.
Aspirin solubility 0.33 g/100 mL.
for an aspirin suspension: zero-order rate
Activation Energy Calculations

Reaction rates are proportional to the number of collisions per unit time.
k0 = 5 x 10-7s-1 x 0.33 g/100 mL =

k0 = 1.65 x 10-7 g/(100mL * s)
shelf life
(0.1)(13)
= 7.9 x 106 s=91 days
-7
1.65 x 10
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the number of collisions increases as the temperature increases.
The reaction rate constant is observed to have an exponential dependence on

temperature described by the Arrhenius equation
k = A exp(-Ea/RT)
k :reaction rate constant
A :constant
Ea: activation energy of the chemical reaction
T : the absolute temperature (t C + 273.16C).
Dose of aspirin: 650 mg/teaspoon(5 mL) = 13 g/100 mL.
t 90 =
log k = log A - Ea/2.303RT
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Estabilidad
TEMPERATURE EFFECTS
Typical Arrhenius plot of log k against 1/T,
60
4.5
4
Eact= 12 Kcal/mol
40
Log K
Energy Kcal/mol
50
20
Estabilidad
TEMPERATURE EFFECTS
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A+B
reactants
1.5
1
3.2
3.4
3.6
3.8
(1/T(K))*1000
Slope= 3.51*103
Ea= 3.51*103*(2.303)*(1.987)=16.1 Kcal/mol
Extent of reaction
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2.5
2
0.5
0
B+C
products
10
3.5
3
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Estabilidad
Estabilidad
TEMPERATURE EFFECTS
TEMPERATURE EFFECTS
Example:
Sulfacetamide.

Compound
Reaction
Ea (kcal/mol)
Ascorbic Acid
Oxidation
23
Aspirin
Hydrolysis
14
Atropine
Hydrolysis
14
Benzocaine
Hydrolysis
19
Chloramphenicol
Hydrolysis
20
Epinephrine
Oxidation
23
Procaine
Hydrolysis
14
Thiamine
Hydrolysis
20
first-order rate constant in the pH-independent region (5-11)

K= 9 x 10-6 s-1 at 120C.
Ea= 22.9 kcal/mol at pH 7.4.
Calculate the shelf life at 25C.
log
k2
Ea 1 1
=

k1 2.303R T2 T1
k 25
= 8.7 x 10-5
k120
Activation Energies for Some Drug Decomposition Reactions
t 90 =
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Estabilidad
log
k 25
1
22900 1
=
k120 (2.3)(1.987) 298 393
k25 = (8.7 x 10-5) (9 x 10-6 s-1)

= 7.85 x 10-10 s-1
0.105
= 1.34 x 108 s
7.85 x 10-10 s-1
4.25 years
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Estabilidad
TEMPERATURE EFFECTS
TEMPERATURE EFFECTS
Example
The following rate constants were determined for 5-fluorouracil
decomposition at pH 9.90.
Answer: (a) from the Arrhenius plot of the data we obtain

The slope
B= -12.31=Ea/R
Ea = 24.5 kcal/mol
106 k (s -1 )
80
0.96
70
0.32
60
0.118
10
1
Log k
t (C)
(a)
(b)
0.1
Determine the activation energy at this pH;

Extrapolate the graph to room temperature (25C) and
determine the rate constant and shelf life at this temperature.
0.01
2.800
2.850
2.900
2.950
3.000
3.050
1/T (K)
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Estabilidad
TEMPERATURE EFFECTS
Q10-Value Calculations:
(b) From extrapolation of the graph to 25C (1/T = 0.00335),

we obtain log k25C = -8.86.
k25C = 1.38 x 10-9 s-1
t90 = 7.6 x 107 s = 2.4 years
Consider the ratio of rate constants kT2/kTl at two temperatures

T1 and T2. Consider T1=T2+10
The quantity Q10 is defined as
10
Q10 =
Log k
k (T +10)
kT
The Q10 factor can be calculated from the next equation:
0.1
Q10 =
0.01
2.800
Estabilidad
2.850
2.900
2.950
3.000
3.050
1/T (K)
k (T +10)
kT
E
= exp a
R
1
1

T
10
T
+
Note that Ea is always positive.

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Estabilidad
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Estabilidad
For an arbitrary change in temperature, T = T2 - T1,
The activation energies for drug decompositions usually fall in the

range 12 to 24 kcal/mol.
Next table gives values of Ea corresponding to three rounded
values of Q10.
These values of Q10 = 2, 3, or 4 to represent low, average, and
high estimates of Q10 when Ea is unknown
Q10 (30 to 20C)
Ea (kcal/mol)
2.0
12.2
3.0
19.4
4.0
24.5
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Q T =
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k (T +T)
kT
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= Q10( T /10)
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Estabilidad
For an arbitrary change in temperature, T = T2 - T1,
E
T (T + 10)
10
Q T = exp a
R
(T
10)(T)
10 (T + T)
+
T
Q T = exp a
R (T + T)(T)
10
= exp a
R (T + 10)(T)1
Multiplying the exponential term by
This equation is exact. However, since T 300K, (T + 10)/(T + T) 1,
E
T
10 (T + 10)
Q T = exp a
R (R + T)(T) 10 (T + 10)
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Q T =
Estabilidad
Estabilidad
(b) a 25 to 0C temperature change.
Answer:
change for:
(a) a 25 to 50C temperature change
(b) a 25 to 0C temperature change.
T = -25,
Answer:
Q25 =
(a) T = +25,
= Q10
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Example Calculate the factors by which rate constants may
k 25
kT
Q10 T /10
k (25+ 25)
k (T +T)
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Q+25 =
[ T /10][(T +10) /(T +T )]
Q T = Q10[ T /10][(T +10) /(T +T )]
10 T + 10
i
10 T + 10
gives
Estabilidad
(25/10)
k (025)
k0
= Q10 ( 25/10)
= 1/5.7, 1/15.6, 1/32 for Q10 = 2, 3, 4, respectively

Thus the rate decreases to between 1/6 and 1/32 of the initial
rate.
= 5.7, 15.6, 32 for Q10 = 2, 3, 4, respectively

Thus the rate increases between 6-fold and 32-fold, with a
probable average increase of about 16-fold.
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Estabilidad
SHELF-LIFE ESTIMATION METHODS
Estabilidad
The expiration date is given for room temperature. What is

the expected extension of the shelf life in a
refrigerator?
Q = 4 provides the largest estimate for the increase in rate

with increasing temperature,
Q = 2 provides the smallest reasonable estimate for the
decrease with decreasing temperature.
Example: Using Q10 = 2, 3, 4, calculate the half-life change from

70C to 25C for methyl paraben at pH 4.
We have T = 25 - 70 = -45,
Q-45= 1/23, (Q10=2)
Q-45= 1/140, (Q10=3)
Q-45= 1/512, (Q10=4)
Since k70C = 1.6 x 10-6 s-1 (from the monograph) then

t (70C) = 4.3 x 107 s = 501 days
t (25C) = 31 yr
= 199 yr
= 709 yr
.
(Q =2)
(Q = 3)
(Q = 4)
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The expiration date is given for refrigeration conditions.

How long may the product be left at room temperature?
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Estabilidad
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Estabilidad
The expiration date is for room-temperature conditions, and it

is desired to heat the product in sterilization. What percent
decomposition can be expected at the higher temperature?
The expiration date is for room-temperature conditions, and it

is desired to heat the product in sterilization. What percent
decomposition can be expected at the higher temperature?
Zero order
t 90 =
0.1[D 0 ]
k0
t 90 (T) =
First order t 90 =
Problems of this type require estimates of the effect of
temperature on the shelf life. Assuming we do not have
exact Ea values available, we use the Q10 values of 2, 3,
and 4 to make such estimates.
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0.105
k1
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a
k (T1 +T)
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Estabilidad
Estabilidad
Example A.
The expiration period for a reconstituted product is 18 h at room
temperature.
Estimate the expiration period when the product is stored in the refrigerator.

t 90 (T2 ) =
a
k T1 iQ10 ( T /10)
or, since t90(T1) = a/kT1:
T = -20C,
t 90 (T2 ) =
t (T )
t 90 (T2 ) = 90( T 1/10)
Q10
18
Q10 ( 20 /10)
(Q = 2)
(Q = 3)
(Q = 4)
conservative estimate would be 72 h and a likely estimate 162 h.
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Estabilidad
t 90 (5 ) =
t90 (5C) = 18 * 22 = 72 h
= 18 *32 = 162 h
= 18 * 42 = 288 h
the estimate of t90(T2) is independent of the order.

a positive T (T2 > T1) reduces the shelf life,
a negative T(T2 < T1) increases it.
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t 90 (T1 )
Q10 ( T /10)
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Estabilidad

Example B.
A newly reconstituted product is labeled to be stable for 24 h in a
refrigerator. What is the estimated shelf life at room temperature?
t90 (5C) = 24 h
If the product has been stored for a known length of time

at another temperature:
1.
compute the time interval at the specified
temperature that would give the equivalent
decomposition to that which occurred at the actual
storage temperature and
2.
subtract this value from or add it to the label date for
a new expiration date.
t 90 (T2 ) =
t 90 (T1 )
Q10 ( T /10)
t 90 (25 ) =
24
Q10 (20 /10)
t90 (25C) = 24/4 = 6 h

(Q = 2)
= 24/9 = 2.7 h
(Q = 3)
= 24/16 = 1.5 h
(Q = 4)
Thus a likely value is about 3 h, with a conservative estimate of
1.5 h and a possible value of 6 h.
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Estabilidad
Estabilidad

Example
The expiration date for a product is one year from the current date when
stored in a refrigerator. The product has been stored-for one month at
room temperature. If the product is now returned to the refrigerator,
what is the new expiration date?
Answer
One month at room temperature would be equivalent to
t 90 (T2 ) =
Example.
The ampicillin monograph in the Physicians' Desk Reference (1) states
that the reconstituted suspension is stable for 14 days in a
refrigerator. If the product is left at room temperature for 12 h, what
is the reduction in the expiration period?
t 90 (T2 ) =
t 90 (T1 )
t 90 (T2 ) Q10 ( T /10)
Q10 ( T /10)
0.5 * 22 = 2 days
(Q = 2)
0.5 * 32 = 4.5 days (Q = 3)
(Q = 4)
0.5 * 42 = 8 days
1 *22 = 4 months
(Q = 2)
1 *32 = 9 months
(Q = 3)
(Q = 4)
1 *42 = 16 months
that is, 4, 9, or 16 months at 5C.
The most likely estimate is 9 months, hence if the product is returned to the
refrigerator, only 3 months would be left.
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t 90 (T1 )
t 90 (T2 ) Q10 ( T /10)
Q10 ( T /10)
The expected reduction is thus 4.5 days.
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Estabilidad
Influencia del pH
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Estabilidad
Influencia del pH
Example1
pH-Rate profile for hydrolysis of citric acid anhydride at 25C

Example:pH-Rate profile for the dehydration of streptovitacin A at 70C
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Estabilidad
D. pH EFFECTS (2). Sigmoid Curves
D. pH EFFECTS (3). Bell-Shaped Curves
Example2: Hydrolysis of aspirin.
Some pH-rate profiles show

maxima, often with a "bell
shaped" peak.
where k3 > kl and k" > k'.

The rate equation is
rate = k1[RCOOH][H+] +
k'[RCOOH] + k"[RCOO-] +
k3[RCOO-][OH-]
The pKa of aspirin is 3.6, so the
plateau region of the curve (pH 4
to 8) is accounted for primarily by
the k" term, that is, hydrolysis of
the anion. This reaction is
responsible for the instability of
aspirin in solution dosage forms
pH-Rate profile for aspirin hydrolysis at 25C
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Catalysis is produced by the monoanion of the catechol derivative,

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Estabilidad
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Estabilidad
Inhibicin de la oxidacin
Hidrlisis
Oxidacin
Racemizacin
Descarboxilacin
Polimerizacin
Descomposicin enzimtica
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Hydrolysis of penicillin G catalyzed

by 3,6-bis (dimethylaminomethyl)catechol.
49
Vas de degraddacin qumica

Estabilidad

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Proteger de la luz
Evitar presencia oxgeno
Uso agentes antioxidantes
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Estabilidad
Antioxidantes sistemas hidrfilos

Antioxidantes sistemas lipfilos
Combinaciones inorgnicas de azufre:

sulfitos (olor y sabor desagradables)
Combinaciones orgnicas de azufre: (olor
y sabor desagradables)
cido ascrbico: tpicas, parenterales,
orales
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cido glico y steres del cido glico

steres cido ascrbico
Butilhidroxianisol(BHA)
Butilhidroxitolueno(BHT)
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Estabilidad
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Estabilidad
Sobredosificacin
Reforzadores de accin: cido fosfrico,

citrco, tartrico
Inactivadores de catalizadores: EDTA
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Naturales: Tocoferoles
Sintticos y semisintticos:
Sinrgicos

Estabilidad

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Antibiticos, vitaminas
Exceso de contenido activo que es
necesario tener en cuenta para garantizar
la estabilidad, es decir, la compensacin
de la prdida de principio activo prevista
durante el periodo de conservacin.
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Estabilidad
Inestabilidad biolgica

Clasificacin conservantes
Conservadores: requisitos
Tolerancia fisiolgica
Compatibilidad
Estabilidad qumica
Olor y sabor
Espectro activo
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Estabilidad

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Fenoles
Alcoholes alifticos y aromticos
Compuestos orgnicos de mercurio
Compuestos de amonio cuaternario
cidos carboxlicos
Otros.
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Estabilidad y Inestabilidad de Los Medicamentos

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Estabilidad y Inestabilidad de Los Medicamentos

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Estabilidad

Contenido en sustancia activa

Caracteristicas esenciales de calidad:

Contenido en sustancia activa

reduccin del 10% en sustancia activa

Alteraciones de los medicamentos

Sobre la sustancia activa

Fecha de caducidad: mes y ao

Estables, seguros, eficaces

Inestabilidad Fsica: alteracin de las

Vias degradacin fsica:

a typical chemical reaction

Reaction rate [D]*[W]

D and W, "colliding" to form one or more product molecules,

the rate of reaction: proportional to the number of collisions a

the number of collisions is proportional to the product of the concentrations of the

we let k2 be the rate constant

Reaction rate [D]*[W]

Reaction rate corresponds to the rate of loss of D and is denoted (d[D]/dt)

Order of reaction: sum of the exponents of

If the water concentration W is held constant (by having a

where k1= k2 [W]

Second order reaction

and the reaction is apparent zero order

[D] = [D]0 e k1t

The shelf-life, t90:

[D] = [D]0 - k0*t

[D] = [D]0 - k0*t

Integrating from t = 0 to t = t with [D] = [D]0 at t = 0,

Example: aspirin (acetylsalicylic acid)

Activation Energy Calculations

k0 = 5 x 10-7s-1 x 0.33 g/100 mL =

the number of collisions increases as the temperature increases.

The reaction rate constant is observed to have an exponential dependence on

Dose of aspirin: 650 mg/teaspoon(5 mL) = 13 g/100 mL.

log k = log A - Ea/2.303RT

Typical Arrhenius plot of log k against 1/T,

first-order rate constant in the pH-independent region (5-11)

Activation Energies for Some Drug Decomposition Reactions

k120 (2.3)(1.987) 298 393

k25 = (8.7 x 10-5) (9 x 10-6 s-1)

Answer: (a) from the Arrhenius plot of the data we obtain

Determine the activation energy at this pH;

(b) From extrapolation of the graph to 25C (1/T = 0.00335),

Consider the ratio of rate constants kT2/kTl at two temperatures

The Q10 factor can be calculated from the next equation:

Note that Ea is always positive.

The activation energies for drug decompositions usually fall in the

Q10 (30 to 20C)

For an arbitrary change in temperature, T = T2 - T1,

Multiplying the exponential term by

This equation is exact. However, since T 300K, (T + 10)/(T + T) 1,

(b) a 25 to 0C temperature change.

Example Calculate the factors by which rate constants may

[ T /10][(T +10) /(T +T )]

Q T = Q10[ T /10][(T +10) /(T +T )]

= 1/5.7, 1/15.6, 1/32 for Q10 = 2, 3, 4, respectively

= 5.7, 15.6, 32 for Q10 = 2, 3, 4, respectively

SHELF-LIFE ESTIMATION METHODS

The expiration date is given for room temperature. What is

Q = 4 provides the largest estimate for the increase in rate

Example: Using Q10 = 2, 3, 4, calculate the half-life change from

Since k70C = 1.6 x 10-6 s-1 (from the monograph) then

The expiration date is given for refrigeration conditions.