Chemical Kinetics and Drug Stability:

Drugs that are decomposing can lose their effectiveness, and on rare occasions they can decompose into a toxic product (tetracycline)

*Chemical reactions result from:--Collisions of molecules with sufficient energy (not every collision results in a decomposition, must have enough energy and the proper orientation) **Strom uses eggs in a basket example**--Rate= Collision frequency X energy factor, X probability factor

*Collision frequency --Concentration--Temperature--Molecule Size

*Energy factor: specific energy for the decomposition to occur.

*Probability factor: Type of reaction, molecular geometry.

*Rate of reaction is proportional to the number of collisions that are occurring

With this slide strom talks about the derivation of the constant K

*Cannot determine the order form the stoichiometry or balanced

equation of a reaction

*How do you know what the order of a reaction is?--Experimentally determined--Objective of study of chemical kinetics of a compound.

--No, this is constantly decreasing over time.--Rate of reaction would proceed most rapidly at the beginning of the reaction--Order would be first order

A graph of this equation looks like this--->

This a logarithmic graph of the above graph

*If the graph of log of concentration vs. time that reaction is FIRST ORDER.--Other orders will be different shapes--Rate constant value is the slope (-K)

For compounding and new drugs, this is very important information. It is important to know how a drug is going to react with other drugs when compounded together.

Once K-value is known we can estimate how much active drug is present at any point in time.

This is known as a semi-log graph.--Here you would directly plot the concentration values and the geometry of the paper converts it to logs, you can quickly see if it is a straight line or a curve.--You cannot just “pick two points” to find the slope, you must take the logs of those points, whereas the other graph you can just pick two points b/c you have already picked two points.

--Need to find k value--We know time, Co and C

K value here is in days^-1

This is a derivation for finding the time it takes for a 50% decomposition or half life.-- t(1/2) = (0.693/k)**Important to note, for any 50% decomposition, this equation can be used to find (T)**--For a drug undergoing first order reaction, the concentration does not effect the half-life, it will always be the same--This is also true for any other percentage change.*For a 10 percent change, t=0.105/k --this is important b/c this determines the expiration date of a medication.

**Keep in mind that these numbers are for the drug outside of the body. Up until the person takes the drug, b/c upon consumption all these values change.**

Zero-Order reaction:

*Note that k= Rate constant (conc./time)

*Concentration vs. Time is a straight line (notice NOT LOGARITHMIC)* If you were to graph this logarithmically and you still

got a straight line then the reaction would be first order.

* In a ZERO-order reaction the half-life depends on the initial concentration!!

Second order kinetics

*As you can see the math gets more complicated here, good news is that VERY few pharmaceutical systems are beyond 2nd order.

We have here initial concentration, the concentration after a period of time, and the ORDER.

For this, Strom is using 10 percent increments of decomposition, and his point is that for a first order reaction, K will be

constant and the rate of decomposition will not change. However, note that this is 10% decomposition (112.5), and then another 10% decomposition (102) of that. IT IS NOT THE SAME AS A 20% DECOMPOSITION.

The above follows this standard equation. *USD standard for the expiration date of a drug is the date after 10% of the drug has degraded.

*This reaction shows an ester drug that is changing with the OH- ion concentration.

This would be a second order reaction.

However, if this reaction were occurring in a buffer system, then the OH- ion concentration would be changing very little, and therefore the reaction would behave much like a first order reaction. This type of reaction, is caller “Apparent First Order.” This type of reaction is very common in pharmaceutical systems.

Complex reactions:

*Notice in this type of equation that the that the K value is K1/K2, which gives you Kc.

*In this type of complex reaction, as the drug degrades we have 2 different compounds that are being produced simultaneously.

*Up to this point we have been seeing compounds that degrade to a final product. However, this reaction shows an intermediate.

This makes intuitive sense, because as A decreases more B is being formed, and as B increases more B is available to be converted into C, so therefore C increases with B up to a point. Then A starts to run out and B begins to deminish. After this point C still continues to increase because it is the final product and there is still un-converted B in the reaction to be used up**For example this could be an example where A is a drug as it enters the body, and C could be the eventual product upon excretion.**

Rate limiting step: Slowest step in a reaction which determines the overall reaction speed.

*B/c the rate constant is is in concentration per time, you should be able to determine that this problem is a zero order reaction

Answer is 1 month.

Catalyst: Will change the rate of a reaction but is not consumed in the reaction; provides different pathway for reaction; lower energy requirement.--Will increase decomposition.

****Very important point****

pH-- Hydronium of hydroxyl ions --Hydronium Ions: Specific acid catalysis--Hydroxyl Ions: Specific base catalysis

This is a pH rate profile, it is log K vs pH

If in the pH profile, if the slope is -1 then that implies that specific acid catalysis is occuring, if the slope of the line is +1 then that is specific base catalysis.

If pH value is less than 4, it is acid catalyzed.

from 4-8 you see base catalyzed

If a pharmaceutical company is making a liquid doasge form of a medication, then this is important information b/c solubility, and stability can be influenced by pH. So in this case you would prepare this drug at pH 4 b/c the k value is the smallest, and the rate of decomposition would be the slowest. However, b/c of solubility you may need to use a different pH.

The sigmoidal shape on the right side of this graph could be the pKa value, and therefore where the ionized and unionized form are changing.

In this case where the “v” shape is shifted over to the left, this means that base catalysis is very strong, b/c even though

OH- ion concentration is low, base catalysis is still occurring. If the “v” is shifted to the right then that means that specific acid catalysis is strong b/c H+ ion concentration is low on the right side of the graph, but acid catalysis is still able to happen. **Read through this a couple of times, it might be easy to get tricked on this for the exam**

This is a first order-reaction, this is log of concentration v time. The steeper the lines are the more rapid the rate of decomposition is. Therefore in this graph, we have the reaction speeding up at lower pH values.

*In the graph, this is a drug in two different buffers. If the total concentration of buffer is increasing*this is known as general acid catalysis.*In specific acid catalysis, hydronium ions are catalyzing the reaction.

*In general acid acid catalysis: any other acid besides hydronium ions are catalyzing the reaction. In this case we do not which ion is catalyzing the reaction. Based on this graph we can say that the base component of the buffer seems to be catalyzing the reaction. *A pharmaceutical company that is using this data to make a drug may want to use less buffer of a different buffer.

Relationship b/t the k value and temperature is expressed through this equation.

*These are some rearrangements of the Arrhenius equation.

This is a first order, log of concentration vs. time graph.

There will be a different k value at each of these three temperatures.

*Here is a graph of our k values, these can be used to determine what the storage temperature of a drug needs to be.

*Once we know our rate constant, then we can determine what our expiration date will be.

*From the information we have, we are able to extrapolate what the k value will be at any other temperature. by using these equations:

A suspension contains insoluble solid material suspended in a liquid vehicle. Some will be dissolved in solution, but there will also be solid material as well.

*This is a saturated solution that will have an equilibrium b/t dissolved drug and solid drug. *Concentration here is constant!--Zero order kinetics, if you are told that you have a drug in suspension, you can assume that it will be zero-order.--IF YOU HAVE A SOLUTION (NOT A SUSPENSION) you can assume that it is degrading by FIRST ORDER kinetics.

--Understand that this is actually a first order reaction, but that suspensions behave as zero-order.

The graph becomes a curve, at the point where there is no longer any solid drug remaining. However, in a practical setting we would never see this b/c the pt would stop taking the drug long before we allowed the drug to degrade to this point.--the point where the graph becomes non-linear, we would actually see first order kinetics at this point. --Again, for solution assume first order, for suspensions assume zero-order.

*Drugs degrade when they are in solution, therefore is stands to reason that if we keep the drug out of the solution, then it will degrade slower, which is why we use common ions to keep the drug in solid form. *In the case of procaine and penicillin, we add the common ion, procaine, which will allow more of the drug to remain in solid form b/c having more dissolved ion in solution will drive the drug to not dissolve **remember the principle of equilibrium here, if the undissolved & dissolved forms are in equilibrium, then adding procaine to the solution will cause more of the procaine penicillin drug to balance the equation by remaining undissolved.

*Light can influence the rate of a reaction and can cause decomposition occur.

Degradation pathways:*Hydrolysis: Most common (stabilized by mimizing the amount of water present.If any of these functional groups are present, you can be fairly certain that decomposition by hydrolysis is going to occur. --Carboxylic acids--esters --amides --imides--lactams--lactones

*Most of the time you cannot tell if a decomposition has occurred by sight or smell.

*Hydrolysis can be catalyzed by hydronium, hydroxide, or any general acid or base.

Oxidation: Involves the removal of electropositive atom or the addition of an electropositive atom --Occurs through a process known as Autoxidation (non-catalyzed, proceeds in the presence of molecular oxygen)

*Process of producing the first free radical is initiated by light, heat, or trace metals*Phenols, catechols, ethers, thiol, aldehyde, nitrites will all degrade via oxidation

These products are highly conjugated. These rxns are actually visual, the products usually turn pink and brown. (but this does not always mean that an oxidation has occurred)

*Isomerization/racemization--Conversion to optical or geometric isomer. --Can be be a problem b/c the drug can be converted to an isomer that is less active,--Stabilized through pH control, reduced temp, changing the solvent, light reducing packing

*Photolysis: This can be either sunlight or normal room light that can cause this type of decomposition.

*Reconstituting drugs, where the solid form is more stable is a way to stabilize them.

*Using pH can be a way to stabilize a drug*If a drug is prone to temperature decomposition Refrigeration can be a way to stop decomposition*If a drug is prone to oxidation: --excluding oxidation would be a good way to slow decomposition--Excluding light--pH control--Excipients (Chelating agent, EDTA, citric acid) --Reducing agents (Sodium thiosulfate)--Anti-Oxidants: *one type is an agent that is preferentially oxidized (The agent is more easily oxidized than the drug, and therefore will take on the bulk of the oxidizing) --> Sodium bisulfite, sodium sulfite, thioglycerol, ascorbic acid (If sulfites are present, you must have a warning label)*Chain terminators -->Thiosorbitol, BHA, BHT, propyl, gallate, alpha-tocopherol (vit. E)

*If a drug is beyond itʼs expiration date it is considered to be “misbranded” and should not be used*If an expiration date is given as a month and year, then the last day of the month is the expiration date.

*A drug for reconstitution has two expiration dates:--One is for dry powder--Other is for reconstituted form

*Responsibility of the Pharmacist --Observe expiration dates (in Georgia you must go through all of the inventory at regular intervals and check)--Store properly --Obsever for evidence of instability--Dispense in proper container--Inform and educate pt.

*Beyond use date vs. expiration dateExpiration Beyond Use

Required by lawDetermined by extensive stability testing

Specified by pharmacist on the label that the pt. receivesDifferent container, so the expiration date is no longer entirely relevant.Not based on extensive testing

*Drug disposal *How do we get rid of unwanted, unused, and store drugs in a safe and environmentally sound way.*Problems: Environmental, source of poisoning, “Pharming” (Where others abuse drugs not prescribed to them), Potential crime, illegal

--However there is a list drugs that should be flushed, most of the drugs on this list are drugs that have a potential for abuse

--Incineration is the primary way the FDA disposes of unused drugs