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In several cases the special nature of a formulation will preclude dilution by an aqueous infusion fluid.
- The interaction between a large organic anion and organic cation may result in formation of relatively insoluble precipitate or phase separation.
the process of an atom an ion is called "ionization".
is Neutral species formed by electrostatic attraction between oppositely charged ion in solution, which are often sufficiently lipophilic to dissolve in nonaqueous solvent.
* Injectable products containing phenytoin , digoxin and diazepam may come into this category if they are formulated in a nonaqueous but water – miscible solvent ( e.g. an alcohol-water mixture ) or as a solubilize (e.g. Micelle ) preparation.
atom loses an electron .
The formation of an ion pair result in :
burying of charges and alteration to
the physical properties.
-The interaction are not always visible the formation of visible precipitate depends to
large extent on the insolubility of the two
combining species in the particular
mixture and the size to which the
precipitate particular grow.
* Addition of the formulation to water may result in precipitation of the drug depending on the final concentration of the drug and solvent .
atom gains an electron
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*The aim of graphical method is to plot diluion curves and solubility curves on the same graph .
-Chemical and physical stability may result
in the changes of pH, buffering capacity, salt formation or complexation.
*A graphical technique has been described to predict whether solubilised drug system will become supersaturated and thus have the potential to percipitate
The pH in a medium, whether
in a formation or in the body can be a primary determent of a drug behavior.
hydrogen ion will be an important determinant of solubility, crystallization and partitioning
**Advantages:
avoids the need to teach the antibody producer tissue culture method.
* When a drug dissolved in a cosolvent system is diluted with water, both drug and cosolvent are diluted.
*This is achieved in, where the dilution curve have been potted semilogarithmically for thee systems containing initially 1,2 and 3 mg.cm of drug substance ( plot l,ll,and lll, respectively).
**Advantages:
avoids and decrease for the laboratory personal experienced in subject handling(like animals).
-when there’s chemical instability it may give
rise to the formation of inactive or toxic products.
ex: -Gastric pH is 1-3 normal in the human stomach.
-The stomach PH changes by ingesting
antacids ,food ,weak electrolytes.
* Addition of this formulation to normal saline result in the formation of the precipitate .
-Gastric secretion can be inhibited by
some drugs.
* With solution lll, dilution below about 30% cosolvent cause the system to be supersaturated.
*With solution ll, below 20% codolvent the solubility line and the
dilution line touch only eith solution containing 1 mg cm can
there be dilution whithout preciptation.
-some additives may change the pH of a
solution or solvent.
* The logarithm of the solubility of a drug in a cosolvent system
generally increase lineary with percentage of cosolvent present
**Disadvantages:
can cause significant pain or distress on
subject.
**Disadvantages:
methods more expensive.
* On dilution, the drug concentration falls linearly whith
a fall in the percentage of cosolvent .
Ex: 500mg of ampicillin sodium can
raise the pH of 500cm3 of some
fluids to over 8.
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presence of both lipophilic and hydrophilic features within structure,
logP < 0.5
water soluble drug
Eg: gentamicin , heparin , streptokinase
Poorly absorption after oral so it given by injection
1-Drug complexation can lead to beneficial properties such as enhanced aqueous solubility
(e.g. theophylline complexation with ethylenediamine to from aminophylline) and stability
(e.g. inclusion complexes of labile drugs with cyclodextrins).
Caffeine + organic acid anions – more water soluble; example complex with xanthine .
Drugs need to dissolve before they can be absorbed ..
• drugs’ molecules which possess balanced solubility is much better absorption.
2- Complexes can alter the pharmacologic activity of the agent by inhibiting interactions with receptors.
logP > 0.5
lipid soluble drug
Absorbed after oral administration
-Measure of lipophilicity .
-Determined by the ratio of the solubility of drug in an organic solvent to the solubility of the same drug in an aqueous solvent
-Which called partition coefficient (P).
Used to discribe dissolution of drug ..
Dm\dt = DA (Cs - C) \ h
1- Surface area and particle size
Eg: antifungal drug griseofulvin
2- pH
Eg: antifungal drug ketoconazole
3- salt
Eg: anti-inflamatory drug & osteoarthritis naproxen
4- crystal form
Eg: antibiotic novobiocin
5- surfactant
Eg: aqueous suspention phenacetin for pain relieving and fever reducing
6- Lipid solubility
Caffeine + organic acids – less soluble but masks the bitter taste of caffeine.
Ex – complex w/ gentisic acid formulated in extended release chewable tablet.
Because there is a need for drugs’ molecules to move through both
-aqueous (plasma,extracellular fluid, cytoplasm, etc.) .
-lipid media (biologic membranes) .
3- In some instances, complexation also can lead to poor solubility or decreased absorption of drugs in the body
- Ionic strength
- Temperature
- pH
- Competing ions
logP > 3
Very lipid soluble drug
- Absorbed but more susceptible metabolizm &
biliary clearance.
-Drugs with LogP value close to 2
able to enter the CNS.
• n-Octanol (lipid phase) have similar properties for
biological membrane
• Phosphate buffer of pH 7.4 (aqueous phase).
• P is often expressed as a log value
Complexation of benzocaine with salicylates will decrease the boavailability of benzocaine while its comlexation with PEG will increase its absorption
4- Complexation also can aid in the optimization of delivery
systems (e.g. ion-exchange resins) and affect the
distribution in the body after systemic administration as
a result of protein binding
Eg: thiopen
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A)-Displacement interactions
competition between Drugs for the binding sites.
A)-Physiochemical characteristics of the drug
Increase in lipophilicity increases the extent of binding
-Acidic drugs bind to HSA
-Basic drug to AAG
-Neutral drug to lipoproteins
1- Reversible
Hydrogen bonds
Hydrophobic bonds
Ionic bonds
Van der waal’s forces
The bound drug is kept in the blood stream While the unbound component may be metabolized or excreted ( making it the active part)
2- Irreversible
Irreversible drug binding, though rare, arises as result of covalent binding and often a reason for carcinogenicity or tissue toxicity of the drug
B)- Competition between drug and normal body constituents
The free fatty acids are known to interact with a number of drugs that bind primarily to HSA.
-Factors relating to the drug
-Factors relating to the protein and other binding component
- Drug interaction
-Patient related factors
B)- concentration of drug in the body
Alternation in the concentration of drug substance as well as protein subsequently brings alternation in the bindin
C)- Allosteric changes in protein molecule
The process involves alteration of the protein structure by the drug or it’s metabolic thereby modifying its
binding capacity
C)- Affinity of a drug for a particular binding component
e.g: Digoxin has more affinity to cardiac muscles
protein as compared to skeletal muscles.
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- changes in pH which lead to precipitation of the drug .
- Ion exchange interaction where ionised drugs interact with oppositely charged resins .
* Drug-drug interactions are modifications of the effects of one drug when used in conjunction with another drug .
- Change f solvent characteristics on dilution, which may also cause precipitation
- Adsorption to excipients and containers causing
loss of drug .
- Cation-anion interactions in which complexes are formed .
*Drug –drug interaction can take place before administration of a drug. These may result in precipitation of the drug from solution, loss of potency or instability .
- The influence of salt on decreasing or increasing solubility, respectively salting-out and salting-in .
- Protein binding to plasma proteins through which the free plasma concentration of drugs’s reduced .
* These interactions, which can result in either an augmentation or diminution of pharmacologic
activity, may account for a significant proportion
of all adverse drug reactions.
- Interaction with plastics and loss of drug .
1-Describe the effect of ionization on drug interaction.
2-undersatd the effects of solvent dilution on drug interaction.
3-diffrenate between PH in vivo and vitro.
4-understand factors that affecting the solubility and dissolution in vivo.
5- summaries the factors affecting protein binding and complexation.
A- more electron than proton.
B-negative ion.
C- more proton than electron.
D-atom gain electron.
A- lipid soluble drug
B- water soluble drug
C- Very lipid soluble drug
D- Not lipid or water soluble
A- solubility
B- stability
C- temperature
D- A & B
1- Physical Pharmacy; by Alexander T. Florence (Author), David Attwood (Author). (2007), pharmaceutical Press. ch:8,p125 .
2- physicochemical principles of pharmacy-6th edition; By alexander taylor florence d. attwood. (2012), pharmaceutical Press, london.
ch:11, p:451
ch:11, p:450
ch:11, p: 444
ch:4, p:153
3- National Research Council (US) Committee on Methods of Producing Monoclonal Antibodies, (Summary of Advantages and Disadvantages of In Vitro and In Vivo Methods) -1999, National Academy of Sciences
a) Drug interaction
b) Factor relating to solubility
c) Factor relating to the drug
d) A-C
A- pH increase ( base media )
B- pH decrease ( acid media )
C- increase lipid solubility of drug
D- decrease lipid solubility of drug
4- Aulton's Pharmaceutics-4th edition; By Michael E. Aulton, Kevin M.G. Taylor. (2013), Churchill Livingstone. ch:20, p:314.
5- artical https://www.corrosionpedia.com/definition/305/complexation
6- http://www.slideshare.net/eckotanglao/complexation-and-protein-binding
7- Handbook of essential pharmacokinetics, pharmacodynamics
and drug metabolism for industrial scientists by; younggil kwon,
2002, kluwer academic. Ch:7, p114