Stability Of Drugs:Effect Of Temperature And Ph On Reaction Kinetics
From Pharmpedia
Temperature
Temperature has a high degree of influence on all varieties of chemical reactions and usually they are accelerated by a raise in temperature. This is understandable as we know that with increased temperature the molecules move faster with increased kinetic energy and the rate of collision of molecules increases. Also, a greater available energy causes more molecules to have enough activation energy and the fraction of collisions with enough energy increases. It is said that typically a 10oc increase in temperature produces a 2 – 5 fold increase in decomposition.
The effect of temperature on the rate constant k is indicated by the Arrhenius equation which
K = Ae-(Ea /RT)
Log k = Log A - Ea/2.303 RT
Where A is a constant that is termed the frequency factor, a is the energy of activation, R is the gas constant and T is the thermodynamic temperature.
For drug compounds whose decomposition is log K is temperature, if log k is plotted against 1/T, a straight line is obtained. This is kown as Arrhenius plot. The constants Ea and A may be determined from the slope and intercept of this line, which are equal to -Ea/2.303R and log A respectively. We usually take on the X axis 1/T x 10-3 and log K on the y axis.
The activation energy Ea is the energy needed to cause reaction and is usually in the range of 15 – 60 k calmol-1 with a mean of 19.8 (Aulton). Values for a wide range of reactions are 10 – 100 kcal not-1 . If we are using Ea in the calculation of shelf life and if we are not sure of this value, we should make a conservative estimate and assume a low value (eg.: 10 kcal mot-1) for it. This assumption gives a shorter shelf life but it is better to avoid any risk to the patient.
Non-Arrhenius behavior, or decreasing decomposition with temperature has been observed in Pharmaceutical systems as is well explained by Banker. This may be attributed to the possible evaporation of solvent, multiple reaction pathways, change in physical form of the formulation when the temperature of the reaction is changed.
A good example for this is the increased rate of decomposition of ampicillin on freezing. Savello and Shangraw showed that for a 1% sodium ampicillin solution in 5% dextrose, the percentage of degradation at 4 hour is approximately 14% at -20oc, compared with 6% at Ooc and 10% at 5oc. This decrease in stability in frozen solutions is most frequently observed when the reaction obeys second or higher order kinetics. For example, the formation of nitrosomorpholine from morpholine and nitrite obeys third – order kinetics and the rate of nitrosation is drastically enhanced in frozen solutions.
This behaviour which is contradictory to our basic understanding of reaction mechanisms was reviewed by Pincock and is discussed in Banker. In reactions following second or higher order kinetics, an increase in rate may be brought about by concentration of the reactants in the liquid phase, the solute molecules being excluded from their lattice when the solution freezes. This may also happen due to a change in pH on freezing.
pH
Acidic and alkaline pH influence the rate of decomposition of most drugs. Many drugs are stable between pH 4 and 8. Weekly acidic and basic drugs show good solubility when they are ionized and they also decompose faster when they are ionized. So if the pH of a drug solution has to be adjusted to improve solubility and the resultant pH leads to instability then a way out of this tricky problem is to introduce a water-miscible solvent into the product. It will increase stability by (a) suppressing ionization, (b) reducing the extreme pH required to achieve solubility, (c) enhancing solubility and (d) reducing the water activity by reducing the polarity of the solvent. For example, 20% propylene glycol is placed in chlordiazepoxide injection for this purpose.
Reactions catalysed by pH are monitored by measuring degradation rates against pH, keeping temperature, ionic strength and solvent concentration constant. Some buffers such as acetate, citrate, lactate, phosphate and ascorbate buffers are utilized to prevent drastic change in pH.
Sometimes pH can have a very serious effect on decomposition. As little as 1 pH unit change in pH can cause a change of ten fold in rate constant. So when we are formulating a drug into a solution we should carefully prepare a pH – decomposition profile and then formulate the solution at a pH which is acceptable physiologically and stability-wise also.
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