Showing posts with label Dispensing. Show all posts
Showing posts with label Dispensing. Show all posts

Wednesday, March 9, 2011

Dispensing

Dispensing refers to the provision of medicine according to the prescription.

Following steps are involved in a Pharmacy setup:

1. Prescription: Medicines recommended by the physician as a remedy
2. Formulation: Darwing and expressing the medicines and ingredients of the prescription
3. Compounding: Preparing and mixing of the ingredients and/or medicines of the prescription
4. Dispensing: Giving the medicines to the patient. Medicines are given in a container with proper labelling. This label helps the patient for subsequent use of the medicine.

Dispensing may also involve the preparation of device for the use of patients.

Extemporaneous dispensing:Extemporaneous dispensing refers to the compounding and dispensing of medicines with little or no preparation in response to the stimulus of one's immediate environment.

Thursday, February 24, 2011

Types of properties of solutions

There are following three types of properties of solution:
1. Additive properties
2. Constitutive properties
3. Colligative properties

Additive properties:
These are the properties which are due to sum of corresponding properties of individual atoms or functional groups within the molecules e.g. molecular weight.

Constitutive property:
These are the properties which depend upon the structural arrangement of atoms within the molecules for example optical properties and surface and interfacial properties.

Colligative property:
These are the properties which depend upon the number of molecules present in solution.
Following are colligative properties of dilute solution:

1. Lowering of vapor pressure
2. Elevation of boiling point
3. Depression of freezing point
4. Osmotic pressure

Monday, January 10, 2011

Pharmaceutical Incompatibility

Introduction:
Incompatibility refers to the inability of something or some process to co-exist with another process or thing.
So, Pharmaceutical incompatibility refers to the inability of a pharmaceutical substance to exist in combination with another pharmaceutical entity.

Types of Incompatibility:
There are three types of incompatibility:
1. Therapeutical incompatibility
2. Chemical incompatibility
3. Pharmaceutical or physical incompability

1. Therapeutical incompatibility:
This incompabitlity is resulted due to the combination of drugs having antagonistic or opposing properties.

2. Chemical incompatibility:
This type of incompatibility is resulted due to the formation of undesirable new product when two or more drugs are combined.

Examples of Chemical incompatibility:
1. Precipitation
2. Colour change
3. Effervescences
4. Decomposition

Types of Chemical Incompatibility:
Chemical incompatibility can be intentional i.e. a prescriber knowingly gives incompatible drugs, or unintentional i.e. prescriber does not know that the drugs are incompatible.

There are two types of chemical incompatibility:

1. Tolerated
In this type of incompatibility, chemical reaction can be reduced by mixing the solution in dilute forms or by changing the order of mixing.

2. Adjusted
In this type of incompatibility, change in the formulation is needed with a compound of equal therapeutic value e.g. in the mixture of caffeine citrate and sodium salicylate, caffeine citrate is replaced with caffeine.

3. Pharmaceutical or physical Incompatibility:
This type of incompatibility results by the slow or immediate formation of decomposed solutions or precipitates, when the drugs are combined in a pharmacy setup or laboratoy.

Examples of Pharmaceutical or physical incompatibility:
1. Insolubility
2. Liquefaction
When the substances with low melting points such as camphor, menthol and thymol  are mixed together, a liquid mixture i.e. eutectic mixture is formed and this process is known as liquefaction.

3. Precipitation
Precipitation can result when the solvent in which the solute is insoluble is added to the solution. Resins are normally not soluble in water. So, the tinctures of resins may form precipitate on addition to water.

4. Immiscibility


Correction of pharmaceutical or physical incompatibiliy:

This can be corrected by using one or more of the following methods:

1. Addition of suspending agents or thickening agents:
In the following prescription tragacanth (mucilage or compound powder) is used as a suspending agent.

Phenacetin 3g
Caffeine 1g
Orange Syrup 12ml
Water upto 90ml

As Phenacetin is an indiffusible substance.

On the other hand, tinctures of resins are made soluble in water by the addition of some thickening agents or with vigorous stirring and shaking.

2. Emulsification:
Water and oil are immiscible in each other and they can be made miscible by the addition of Emulsions. This is known as Emulsification.

3. Changing the mixing or order of prescription

4. Changing the form of ingredients i.e. from liquid to solid form or from hydrous form to anhydrous form:
This is often helpful in increasing the solubility of a substance e.g.a solution of ephedrine sulfate, an alkaloidal salt, and liquid paraffin is not possible as alkaloidal salt of ephedrine sulfate is not soluble in liquid paraffin but anhydrous form of ephedrine is soluble in it. So we use anhydrous form.

Examples of Incompatibility:
1. Acids are incompatible with alkaline salts, carbonates and oxides. They causes the precipitation of albumin. So, acids are prescribed alone.

2. Bases and alkaline carbonates must not be prescribed alongwith other drugs in solution. They may precipitate metallic and alkaloidal salts.

Bibliography:
A text-book of materia medica and pharmacy for medical students

**REPRINT** Introduction to materia medica and pharmacology, including the elements of medical pharmacy, prescription writing, medical Latin, toxicology, and methods of local treatment


Survey of active pharmaceutical ingredients-excipient incompatibility: Nature and mechanism

Incompatibilities in prescriptions: For students in pharmacy and medicine and practicing pharmacists and physicians

Prescription writing: Including weights and measures, preparation of solutions, doses, administration and incompatibilities

Davis's Drug Guide for Nurses

Wednesday, June 2, 2010

Extraction and maceration

Extraction:
Extraction is the process of separation of medicinally active substances of plant or animal from a mixture by a mechanical or chemical action such as by distillation or pressure.
This separation is done with the help of dissolving one or more of the substances in a solvent in which it is easily soluble and are separated on the basis of their physical or chemical properties.

Forms of Extraction:

Liquid-liquid Extraction:
It is also referred to as Solvent extraction or Partitionaing. Often the solute is miscible in one solvent and immiscible in the other solvent and this thing is used in the process of Solvent extraction.
If the solute is present in an aquous solvent than it can be separated by pouring another solvent in this solution which is immiscible with the previous solvent. The solute will also be dissolved in the other solvent and in this way the solute will be easily separated by separating one of the solvents.

In solvent extraction, two immiscible liquids are shaken together. The more polar solutes dissolve preferentially in the more polar solvent, and the less polar solutes in the less polar solvent based on the famous statement "like dissolves like".
With the help of liquid-liquid extraction, the standard of a chemical is improved after a chemical reaction.

Instrument used:
Separating funnel is used in laboratories.

Uses of Solvent Extraction:
Solvent extraction is used in
1. Ore processing,
2. Nuclear reprocessing, 
3. The processing of perfumes,
4. The production of fine organic compounds,
5. The production of vegetable oils and biodiesel, and other industries.

Measures of effectiveness

Distribution ratio (D):
Distribution ratio is also referred to as partition co-efficient. This ratio gives indication of the quality of extraction. Distribution ratio is the ratio of concentration of a solute in organic phase and the concentration of the same solute in aquous phase.

D = Conc. of solute in organic phase / conc. of solute in aquous phase

Distribution ratio is dependent on the temperature, concentration of the chemical entities in the system and some other parameters in and around the system.

Separation Factor:
The ratio of two distribution ratios is the separation factor.

Separation factor = Distribution ratio for one solute / Distribution ratio for the other solute

With the help of this ratio, it is easy to assess the ability of the system to separate two solutes.

Decontamination factor:
This factor is used to represent the ability of a process to remove an impurity or contaminant from a product.
Techniques

Batchwise single stage extractions

This is commonly used on the small scale in chemical labs. It is normal to use a separating funnel. For instance, if a chemist were to extract anisole from a mixture of water and 5% acetic acid using ether, then the anisole will enter the organic phase. The two phases would then be separated.
The acetic acid can then be scrubbed (removed) from the organic phase by shaking the organic extract with sodium bicarbonate. The acetic acid reacts with the sodium bicarbonate to form sodium acetate, carbon dioxide, and water.

Multistage countercurrent continuous processes


These are commonly used in industry for the processing of metals such as the lanthanides; because the separation factors between the lanthanides are so small many extraction stages are needed. In the multistage processes, the aqueous raffinate from one extraction unit is fed to the next unit as the aqueous feed, while the organic phase is moved in the opposite direction. Hence, in this way, even if the separation between two metals in each stage is small, the overall system can have a higher decontamination factor.
Multistage countercurrent arrays have been used for the separation of lanthanides. For the design of a good process, the distribution ratio should be not too high (>100) or too low (<0.1) in the extraction portion of the process. It is often the case that the process will have a section for scrubbing unwanted metals from the organic phase, and finally a stripping section to obtain the metal back from the organic phase.
Multistage Podbielniak contactor centrifuges produce three to five stages of theoretical extraction in a single countercurrent pass, and are used in fermentation-based pharmaceutical and food additive production facilities.

Extraction without chemical change

Some solutes such as noble gases can be extracted from one phase to another without the need for a chemical reaction. This is the simplest type of solvent extraction. When a solvent is extracted, two immiscible liquids are shaken together. The more polar solutes dissolve preferentially in the more polar solvent, and the less polar solutes in the less polar solvent. Some solutes that do not at first sight appear to undergo a reaction during the extraction process do not have distribution ratio that is independent of concentration. A classic example is the extraction of carboxylic acids (HA) into nonpolar media such as benzene. Here, it is often the case that the carboxylic acid will form a dimer in the organic layer so the distribution ratio will change as a function of the acid concentration (measured in either phase).
For this case, the extraction constant k is described by k = [[HAorganic]]2/[[HAaqueous]]

Solvation mechanism

Using solvent extraction it is possible to extract uranium, plutornium, or thorium from acid solutions. One solvent used for this purpose is the organophosphate tri-n-butyl phosphate. The PUREX process that is commonly used in nuclear reprocessing uses a mixture of tri-n-butyl phosphate and an inert hydrocarbon (kerosene), the uranium(VI) are extracted from strong nitric acid and are back-extracted (stripped) using weak nitric acid. An organic soluble uranium complex [UO2(TBP)2(NO3)2] is formed, then the organic layer bearing the uranium is brought into contact with a dilute nitric acid solution; the equilibrium is shifted away from the organic soluble uranium complex and towards the free TBP and uranyl nitrate in dilute nitric acid. The plutonium(IV) forms a similar complex to the uranium(VI), but it is possible to strip the plutonium in more than one way; a reducing agent that converts the plutonium to the trivalent oxidation state can be added. This oxidation state does not form a stable complex with TBP and nitrate unless the nitrate concentration is very high (circa 10 mol/L nitrate is required in the aqueous phase). Another method is to simply use dilute nitric acid as a stripping agent for the plutonium. This PUREX chemistry is a classic example of a solvation extraction.
Here in this case DU = k TBP2[[NO3]]2

Ion exchange mechanism

Another extraction mechanism is known as the ion exchange mechanism. Here, when an ion is transferred from the aqueous phase to the organic phase, another ion is transferred in the other direction to maintain the charge balance. This additional ion is often a hydrogen ion; for ion exchange mechanisms, the distribution ratio is often a function of pH. An example of an ion exchange extraction would be the extraction of americium by a combination of terpyridine and a carboxylic acid in tert-butyl benzene. In this case
DAm = k terpyridine1carboxylic acid3H+−3
Another example is the extraction of zinc, cadmium, or lead by a dialkyl phosphinic acid (R2PO2H) into a nonpolar diluent such as an alkane. A non-polar diluent favours the formation of uncharged non-polar metal complexes.
Some extraction systems are able to extract metals by both the solvation and ion exchange mechanisms; an example of such a system is the americium (and lanthanide) extraction from nitric acid by a combination of 6,6'-bis-(5,6-dipentyl-1,2,4-triazin-3-yl)-2,2'-bipyridine and 2-bromohexanoic acid in tert-butyl benzene. At both high- and low-nitric acid concentrations, the metal distribution ratio is higher than it is for an intermidate nitric acid concentration.

Ion pair extraction

It is possible by careful choice of counterion to extract a metal. For instance, if the nitrate concentration is high, it is possible to extract americium as an anionic nitrate complex if the mixture contains a lipophilic quaternary ammonium salt.
An example that is more likely to be encountered by the 'average' chemist is the use of a phase transfer catalyst. This is a charged species that transfers another ion to the organic phase. The ion reacts and then forms another ion, which is then transferred back to the aqueous phase.
For instance, the 31.1 kJ mol−1 is required to transfer an acetate anion into nitrobenzene, while the energy required to transfer a chloride anion from an aqueous phase to nitrobenzene is 43.8 kJ mol−1. Hence, if the aqueous phase in a reaction is a solution of sodium acetate while the organic phase is a nitrobenzene solution of benzyl chloride, then, when a phase transfer catalyst, the acetate anions can be transferred from the aqueous layer where they react with the benzyl chloride to form benzyl acetate and a chloride anion. The chloride anion is then transferred to the aqueous phase. The transfer energies of the anions contribute to that given out by the reaction.
A 43.8 to 31.1 kJ mol−1 = 12.7 kJ mol−1 of additional energy is given out by the reaction when compared with energy if the reaction had been done in nitrobenzene using one equivalent weight of a tetraalkylammonium acetate.

Kinetics of extraction

It is important to investigate the rate at which the solute is transferred between the two phases, in some cases by an alteration of the contact time it is possible to alter the selectivity of the extraction. For instance, the extraction of palladium or nickel can be very slow because the rate of ligand exchange at these metal centers is much lower than the rates for iron or silver complexes.

Aqueous complexing agents

If a complexing agent is present in the aqueous phase then it can lower the distribution ratio. For instance, in the case of iodine being distributed between water and an inert organic solvent such as carbon tetrachloride then the presence of iodide in the aqueous phase can alter the extraction chemistry.
Instead of D_{\mathrm{I}^{+2}} being a constant it becomes D_{\mathrm{I}^{+2}} = k[[I2.Organic]]/[I2.Aqueous] [[I-.Aqueous]]
This is because the iodine reacts with the iodide to form I3-. The I3- anion is an example of a polyhalide anion that is quite common.

Industrial process design

In a typical scenario, an industrial process will use an extraction step in which solutes are transferred from the aqueous phase to the organic phase; this is often followed by a scrubbing stage in which unwanted solutes are removed from the organic phase, then a stripping stage in which the wanted solutes are removed from the organic phase. The organic phase may then be treated to make it ready for use again.
After use, the organic phase may be subjected to a cleaning step to remove any degradation products; for instance, in PUREX plants, the used organic phase is washed with sodium carbonate solution to remove any dibutyl hydrogen phosphate or butyl dihydrogen phosphate that might be present.

Equipment

Two layers separating during a liquid-liquid extraction.  An organic MTBE solution is extracted with aqueous sodium bicarbonate solution. This base removes benzoic acid as benzoate but leaves non-acidic benzil
(yellow) behind in the upper organic phase.
While solvent extraction is often done on a small scale by synthetic lab chemists using a separatory funnel or Craig apparatus, it is normally done on the industrial scale using machines that bring the two liquid phases into contact with each other. Such machines include centrifugal contactors, thin layer extractors, spray columns, pulsed columns, and mixer-settlers.

Solid-Phase Extraction:
It is one of the most important form of extraction for the purification and separation of a large number of chemicals on small scale like in laboratory.
In this process, the substance is dissolved in a solvent and is passed throught a bed or layer of adsorbent having uniform particle sizes. The substance is separated either by adsorption of the solvent or the substance itself into the adsorbent.

Types of Extraction techniques:
1. Continuous Extractions
2. Batch Extractions
3. Extractions involving partition between two immiscible liquids

Questions and Answers:
Q: What is extraction?

Ans: Extraction is withdrawal of dissolved constituents from crude drugs through the use of selective solvent in which the desired constituents are soluble.

Q: What are the processes of extraction?
Ans: The principle methods of drug extractions are,

• Maceration

• Percolation

Frequently a combination of percolation and maceration is used in extraction.

Q: What is maceration?
Ans: The word maceration comes from a latin word “macerare” meaning “to soak”.

Q: What is the principle of maceration?
Ans: It is a process in which the properly comminuted drug is permitted to soak in menstruum until the cellular structure is softened and penetrated by the menstruum and the soluble constituents are dissolved.

Q: How soluble contents are settled down in Maceration?
Ans: As the soluble constituents dissolved in the menstrum, they tend to settle to the bottom as a result of an increase in the specific gravity of the liquid due to its added weights.

Q: In which type of drugs Maceration is used?
Ans: For drugs containing little or no cellular material such as benzoin, aloe, and tolu, which dissolve almost completely in the menstruum, maceration is the most efficient method of extraction

Q: On which temperature Maceration is performed?
Ans: Maceration is usually conducted at a temperature of 15-20 C for 3-5 days or until the soluble matter is dissolved.

Q: Why dipping is essential in Maceration?
Ans: Occasional dipping of the drug bag may facilitate the speed of extraction.

Q: What do you mean by menstruum?
Ans: Menstruum refers to the solvent, which is used to extract ingredients from plant or animal origin.

Further Reading:
Remington: The Science and Practice of Pharmacy (Remington the Science and Practice of Pharmacy)

British Pharmacopoeia 2010

Textbook of Pharmaceutics

Percolation

Q: What is percolation?

Ans: Percolation is the package of the raw material into a column and the solvent is allowed to percolate through it.

Although some materials may be packed into a percolator in the dry state e.g. Ginger, most drugs require preliminary moistening.

Q: What is the principle of percolation?
Ans: It is a process in which a comminuted drug is extracted of its soluble constituents by the slow passage of the suitable solvents through the column of a drug.

Q: What do you know about percolator and percolate?
Ans: The drug is packed in a special extraction apparatus termed as percolator with the collective extractive called the percolate.

Q: What is preliminary moistening?
Ans: The solid material is mixed with sufficient amount of solvent and the moist mass is allowed to stand for 4 hours in a well-closed vessel. This is preliminary moistening.

Q: Why preliminary moistening important?
Ans: This preliminary moistening is important because the dried tissues may swell on contact with the solvent and if packed in the dry condition subsequent swelling might decrease the porosity of the material and choke the column.

Preliminary moistening also makes the fine particles less liable to be washed out of the column during percolation.

Q: Defined the methods of percolation?
Ans: There are two methods of percolation which are given below:

• Commercial scale

• Small scale

Q: What is the commercial method for the percolation?
Ans: The drug is supported on a preforated metal plate covered with sacking or straw. The top of the apparatus is removable and provided with portholes for inspection and running in of solvent. At the base the outlet is fitted with a tap and a pipe leads the top of a second percolator in order to use the solvent more efficiently.

Q: What is the small scale method for percolation?
Ans: On small scale glass percolators can be used and the raw material is supported in a loose plug of tow or other suitable substance which has been previously moistened with solvent.
Q: What is reserved percolation?
Ans: Liquid extracts are more concentrated preparations than tinctures and percolation to exhaustion will produce a preparation that is much diluted. It is therefore necessary to decrease the volume of the percolate by evaporation.

In certain instances such as in Liquorice Liquid Extract, the whole of the percolate may be concentrated by evaporation.

Q: How Ipecac syrup is prepared?
Ans: Ipecac syrup is prepared by percolation. It is prepared by adding glycerin and syrup to an extractive of powdered ipecac obtained by percolation.

The drug ipecac which consists of the dried rhizome and roots of Cephaelis ipecacuanha containing emetine, cephaeline and psychotrine. These ingredients are extractive from the powdered ipecac by percolation with the hydro-alcoholic solvent.

Further Reading:
Remington: The Science and Practice of Pharmacy (Remington the Science and Practice of Pharmacy)

British Pharmacopoeia 2010

Textbook of Pharmaceutics

Extracts

Q: Define Extract?

Ans: Extracts are defined as concentrated preparation of vegetable or animal drugs obtained by removal of active constituents of the respective drug with menstruum, evaporation of all or nearly all of solvent, and adjustment of the residual masses or powders to the prescribed Standards.

Q: How many types of extracts are there?
Ans:
There are three types of extracts:

• Semi liquid

• Solid extracts (Plastic masses)

• Powdered extracts (Dry powder)

Q: How the extracts are mostly prepared?
Ans: Mostly, extracts are prepared by extracting the drug by percolation.

Q: Why extracts are to be protected from heat?
Ans: The use of heat is avoided where possible because of potential injurious of active constituents

Q: Give some examples of extracts.
Ans: The examples of extracts are

• Extracts of Pure glycyrrhiza

• Extracts of Belladonna

Q: Define Fluid Extract?
Ans: USP define Fluid extract as being preparation of vegetable drugs containing alcohol as solvent or as a preservative or both, so that unless otherwise specified in an individual monograph, each milliliter contains the therapeutic constituents of 1g of the standard drug it represents.

Q: How unwanted colloidal material is separated and removed from fluid extract?
Ans: The fluid extract can be separated from the oil, concentrated by evaporation and re-extracted with strong alcohol to removed unwanted colloidal material.

Q: How degradation of fluid extract can occur?
Ans: Fluid extracts are subject to degradation by enzyme action.

Q: How degradation by enzyme is inhibited?
Ans: This can be inhibited by including alcohol to give a concentration of 25% or more but enzyme is not destroyed and concentration must be taken to avoid subsequent condition in which the enzyme activity can be restored.

Q: What are the Solvents and their advantages used in fluid extract?
Ans: Solvents used in fluid extract are

• Alcohol

• Water

• Solvent ether

Acetic acid

Advantages of water and/or alcohol:

• It is cheap.

• It is non toxic.

• It can dissolve wide range of chemical substances.

• It flame and non-flamable.

Further Reading:
Remington: The Science and Practice of Pharmacy (Remington the Science and Practice of Pharmacy)

British Pharmacopoeia 2010

Thursday, May 13, 2010

Suspensions

In chemistry, a suspension is a heterogeneous fluid containing solid particles that are sufficiently large for sedimentation. Usually they must be larger than 1 micrometer. The internal phase (solid) is dispersed throughout the external phase (fluid) through mechanical agitation, with the use of certain excipients or suspending agents. Unlike colloids, suspensions will eventually settle. An example of a suspension would be sand in water. The suspended particles are visible under a microscope and will settle over time if left undisturbed. This distinguishes a suspension from a colloid, in which the suspended particles are smaller and do not settle.Colloids and suspensions are different from solutions, in which the dissolved substance (solute) does not exist as a solid, and solvent and solute are homogeneously mixed.
A suspension of liquid droplets or fine solid particles in a gas is called an aerosol or particulate. In the atmosphere these consist of fine dust and soot particles, sea salt, biogenic and volcanogenic sulfates, nitrates, and cloud droplets.
Suspensions are classified on the basis of the dispersed phase and the dispersion medium, where the former is essentially solid while the latter may either be a solid, a liquid, or a gas.
In modern chemical process industries, high shear mixing technology has been used to create many novel suspensions.
Suspensions are unstable from the thermodynamic poin of view; however, they can be kinetically stable over a large period of time, which determines their shelf life. This time span needs to be measured to ensure the best product quality to the final consumer. “Dispersion stability refers to the ability of a dispersion to resist change in its properties over time.” D.J. McClements.

Destabilisation phenomenon of dispersion:
These destabilisations can be classified into two major processes:
1-Migration phenomena : whereby the difference in density between the continuous and dispersed phase, leads to gravitational phase separation. In the case of suspensions sedimentation occurs as the dispersed phase is denser than the continuous phase.
2-Particle size increase phenomena: whereby the suspended particles join together and increase in size. Below are the two types of this phenomena.
  • reversibly (flocculation)
  • irreversibly (aggregation)
 Technique monitoring physical stability:
Multiple light scattering coupled with vertical scanning is the most widely used technique to monitor the dispersion state of a product, hence identifying and quantifying destabilisation phenomena. It works on concentrated dispersions without dilution. When light is sent through the sample, it is backscattered by the particles. The backscattering intensity is directly proportional to the size and volume fraction of the dispersed phase. Therefore, local changes in concentration (sedimentation) and global changes in size (flocculation, aggregation) are detected and monitored.

Accelerating methods for shelf life protection:
The kinetic process of destabilisation can be rather long (up to several months or even years for some products) and it is often required for the formulator to use further accelerating methods in order to reach reasonable development time for new product design. Thermal methods are the most commonly used and consists in increasing temperature to accelerate destabilisation (below critical temperatures of phase inversion or chemical degradation). Temperature affects not only the viscosity, but also interfacial tension in the case of non-ionic surfactants or more generally interactions forces inside the system. Storing a dispersion at high temperatures enables to simulate real life conditions for a product (e.g. tube of sunscreen cream in a car in the summer), but also to accelerate destabilisation processes up to 200 times.
Mechanical acceleration including vibration, centrifugation and agitation are sometimes used. They subject the product to different forces that pushes the particles / droplets against one another, hence helping in the film drainage. However, some emulsions would never coalesce in normal gravity, while they do under artificial gravity. Moreover, segregation of different populations of particles have been highlighted when using centrifugation and vibration.
Objective Type Questions for Suspensions in Pharmaceutics
1.    A pharmaceutical suspension is defined as a ………………….. ,in which insoluble drug particles are dispersed in liquid medium .                     
 ----------------------
2.    In suspensions ,the partical size ranges b/w…………………..
-----------------------
3.    Following is not the important reason of the suspensions :

a) drug stability      
b) taste improving     
c) taste masking    
d) compatibility                
-----------------------
4.    Suspensions are preferred over tablets & capsules due to     …………………in dosage forms -----------------------
5.    The particle size is important while determining the rate of ……………………..          
-----------------------
6.    During sedimentation , not to form a ………………… is an important feature of the good suspension -----------------------
7.    A good suspension should be resistant to………………….
-----------------------
8.    The ……………….. of a good suspension should not be too much to pour.                        
-----------------------
9.    Such suspensions which are prepared just before dispensing to the patients are called …………………..                                                  
-----------------------
10.    Extemporaneous suspensions are prepared from:  

a)    tablets & capsules
b)    just before dispensing to the patient
c)    contents are crushed in mortar & pestle and a proper vehicle is added
-----------------------
11.For preparation of the extemporaneous  suspensions  , a good quality suspending agent is added which is :

a) cheep  in cost
b) less liable to microbial attack
c) less liable to be coagualated                                                          
------------------------
12.   Carboxymethyl cellulose  is an important …………………………. Used in preparation of the extemporaneous suspensions                                                 
------------------------
13.   USP designs the extemporaneous suspensions as ………………………..          
------------------------
14.    Paediatric antibiotics suspensions are best examples of the ………………………
------------------------
15. Reconstituted suspensions are also called as   ……………………………..                               
------------------------
16.  Reconstituted suspensions are designated by usp as…………………………                     
------------------------
17.    While preparing reconstituted suspensions ;active agents ,sweeteners, colorants ,flavouring agents ,stabilizers, suspending agents are mixed to prepare a ………………powder.                             
------------------------
18.    Previously boiled  & cooled  water is added in …………………………… while preparing ------------------------
19.  The commercial reconstituted suspensions available  is ……………………..                   
------------------------
20.     The condition in which the particles don’t aggregate and in which they remain uniformly distributed throughout the distributed throughout the dispersion and donot settle is celled …………………….                                           
------------------------
21.   Rate of the sedimentation is determined while preparing  by ………………. Law .                           
------------------------
22.  while preparing suspensions , all factors are adjusted so that the rate of the sedimentation is ……………..                       

a) maximum             
b) minimum     
c) medium                                   
------------------------
23.    While preparing the suspensions , the relation b/w density and sedimentation  is …………………                          
------------------------
24.     The particle size of the dispersed phase of the suspensions ranges b/w …………………….            

a) 1 to 50 µm      
b) 2 to 10 mm          
c) 1 to 10 µm
------------------------
Answers to Objective Type Questions for Suspensions in Pharmaceutics

1. coarse dispersion
2. 10-15micrometer
3. b
4. flexibility
5. sedimentation
6. hard cake
7. microbial attack
8. viscosity
9. Extemporaneous suspensions
10. a
11. b
12. suspending agent
13. ORAL  SUSPENSIONS
14. extemporaneous suspensions
15. powders for oral suspensions
16. for oral suspensions
17. homogenous
18. reconstituted suspension
19. Barium sulphate
20. physical stability
21. stokes'
22. b
23. inverse
24. a

(These Objective type questions are helpful for the preparation of Pharmacy Exams)
------------------------
Further Reading:



Monday, May 10, 2010

Colloids and Emulsions

An emulsion is a mixture of two or more immiscible (unblendable) liquids. Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion tends to imply that both the dispersed and the continuous phase are liquid. In an emulsion, one liquid (the dispersed phase) is dispersed in the other (the continuous phase).

Examples of emulsions include vinaigrettes, the photo-sensitive side of photographic film, milk and cutting fluid for metal working.



Structure and properties of emulsions:
It is still common belief that emulsions basically do not display any structure, i.e., the droplets (or in case of dispersions, particles) dispersed in the liquid matrix (the “dispersion medium”) are assumed to be statistically distributed. Therefore, for emulsions (like for dispersions) usually percolation theory is assumed to appropriately describe their properties.

However, percolation theory can only be applied if the system it should describe is in or close to thermodynamic equilibrium. There are very few studies about the structure of emulsions (dispersions), although they are plentiful in type and in use all over the world in innumerable applications.

In the following, only such emulsions will be discussed with a dispersed phase diameter of less than 1 µm. To understand the formation and properties of such emulsions (including dispersions), it must be considered, that the dispersed phase exhibits a "surface," which is covered ("wet") by a different "surface" which hence are forming an interface (chemistry). Both surfaces have to be created (which requires a huge amount of energy), and the interfacial tension (difference of surface tension) is not compensating the energy input, if at all.


Appearance and properties
Emulsions are made up of a dispersed and a continuous phase; the boundary between these phases is called the interface. Emulsions tend to have a cloudy appearance, because the many phase interfaces scatter light that passes through the emulsion. Emulsions are unstable and thus do not form spontaneously. The basic color of emulsions is white. If the emulsion is dilute, the Tyndall effect will scatter the light and distort the color to blue; if it is concentrated, the color will be distorted towards yellow. This phenomenon is easily observable on comparing skimmed milk (with no or little fat) to cream (high concentration of milk fat). Microemulsions and nanoemulsions tend to appear clear due to the small size of the disperse phase.

Energy input through shaking, stirring, homogenizing, or spray processes are needed to initially form an emulsion. Over time, emulsions tend to revert to the stable state of the phases comprising the emulsion; an example of this is seen in the separation of the oil and vinegar components of Vinaigrette, an unstable emulsion that will quickly separate unless shaken continuously.

Whether an emulsion turns into a water-in-oil emulsion or an oil-in-water emulsion depends on the volume fraction of both phases and on the type of emulsifier. Generally, the Bancroft rule applies: emulsifiers and emulsifying particles tend to promote dispersion of the phase in which they do not dissolve very well; for example, proteins dissolve better in water than in oil and so tend to form oil-in-water emulsions (that is they promote the dispersion of oil droplets throughout a continuous phase of water).

Instability
There are three types of instability: flocculation, creaming, and coalescence. Flocculation describes the process by which the dispersed phase comes out of suspension in flakes.Coalescence is another form of instability, which describes when small droplets combine to form progressively larger ones. Emulsions can also undergo creaming, the migration of one of the substances to the top (or the bottom, depending on the relative densities of the two phases) of the emulsion under the influence of buoyancy or centripetal force when a centrifuge is used.

Surface active substances (surfactants) can increase the kinetic stability of emulsions greatly so that, once formed, the emulsion does not change significantly over years of storage. A Non-Ionic surfactant solution can become self-contained under the force of its own surface tension, remaining in the shape of its previous container for some time after the container is removed. Superfluids flow with zero friction and can escape their containers; an ionic solution tends to retain its current shape.

“Emulsion stability refers to the ability of an emulsion to resist change in its properties over time.” D.J. McClements.

Technique monitoring physical stability
Multiple light scattering coupled with vertical scanning is the most widely used technique to monitor the dispersion state of a product, hence identifying and quantifying destabilisation phenomena. It works on concentrated emulsions without dilution. When light is sent through the sample, it is backscattered by the droplets. The backscattering intensity is directly proportional to the size and volume fraction of the dispersed phase. Therefore, local changes in concentration (Creaming) and global changes in size (flocculation, coalescence) are detected and monitored.

Accelerating methods for shelf life prediction
The kinetic process of destabilisation can be rather long (up to several months or even years for some products) and it is often required for the formulator to use further accelerating methods in order to reach reasonable development time for new product design. Thermal methods are the most commonly used and consists in increasing temperature to accelerate destabilisation (below critical temperatures of phase inversion or chemical degradation). Temperature affects not only the viscosity, but also interfacial tension in the case of non-ionic surfactants or more generally interactions forces inside the system. Storing a dispersion at high temperatures enables to simulate real life conditions for a product (e.g. tube of sunscreen cream in a car in the summer), but also to accelerate destabilisation processes up to 200 times.

Mechanical acceleration including vibration, centrifugation and agitation are sometimes used. They subject the product to different forces that pushes the droplets against one another, hence helping in the film drainage. However, some emulsions would never coalesce in normal gravity, while they do under artificial gravity. Moreover segregation of different populations of particles have been highlighted when using centrifugation and vibration.

Emulsifier
An emulsifier (also known as an emulgent) is a substance which stabilizes an emulsion by increasing its kinetic stability. One class of emulsifiers is known as surface active substances, or surfactants. Examples of food emulsifiers are egg yolk (where the main emulsifying agent is lecithin), honey, and mustard, where a variety of chemicals in the mucilage surrounding the seed hull act as emulsifiers; proteins and low-molecular weight emulsifiers are common as well. Soy lecithin is another emulsifier and thickener. In some cases, particles can stabilize emulsions as well through a mechanism called Pickering stabilization. Both mayonnaise and Hollandaise sauce are oil-in-water emulsions that are stabilized with egg yolk lecithin or other types of food additives such as Sodium stearoyl lactylate.

Detergents are another class of surfactant, and will physically interact with both oil and water, thus stabilizing the interface between oil or water droplets in suspension. This principle is exploited in soap to remove grease for the purpose of cleaning. A wide variety of emulsifiers are used in pharmacy to prepare emulsions such as creams and lotions. Common examples include emulsifying wax, cetearyl alcohol, polysorbate 20, and ceteareth 20. Sometimes the inner phase itself can act as an emulsifier, and the result is nanoemulsion - the inner state disperses into nano-size droplets within the outer phase. A well-known example of this phenomenon, the ouzo effect, happens when water is poured in a strong alcoholic anise-based beverage, such as ouzo, pastis, arak or raki. The anisolic compounds, which are soluble in ethanol, now form nano-sized droplets and emulgate within the water. The colour of such diluted drink is opaque and milky.


In pharmaceutics, hairstyling, personal hygiene and cosmetics, emulsions are frequently used. These are usually oil and water emulsions, but which is dispersed and which is continuous depends on the pharmaceutical formulation. These emulsions may be called creams, ointments,liniments (balms), pastes, films or liquids, depending mostly on their oil and water proportions and their route of administration. The first 5 are topical dosage forms, and may be used on the surface of the skin, transdermally, ophthalmically, rectally or vaginally. A very liquidy emulsion may also be used orally, or it may be injected using various routes (typically intravenously or intramuscularly). Popular medicated emulsions include calamine lotion, cod liver oil, Polysporin, cortisol cream, Canesten and Fleet.
Microemulsions are used to deliver vaccines and kill microbes.Typically, the emulsions used in these techniques are nanoemulsions of soybean oil, with particles that are 400-600 nm in diameter. The process is not chemical, as with other types of antimicrobial treatments, but mechanical. The smaller the droplet, the greater the surface tension and thus the greater the force to merge with other lipids. The oil is emulsified using a high shear mixer with detergents to stabilize the emulsion, so when they encounter the lipids in the membrane or envelope of bacteria or viruses, they force the lipids to merge with themselves. On a mass scale, this effectively disintegrates the membrane and kills the pathogen. This soybean oil emulsion does not harm normal human cells nor the cells of most other higher organisms. The exceptions are sperm cells and blood cells, which are vulnerable to nanoemulsions due to their membrane structures. For this reason, these nanoemulsions are not currently used intravenously. The most effective application of this type of nanoemulsion is for the disinfection of surfaces. Some types of nanoemulsions have been shown to effectively destroy HIV-1 and various tuberculosis pathogens, for example, on non-porous surfaces.

Uses:
Emulsions are mainly used in many major chemical industries. In the pharmaceutical industry they are used to make medicines with a more appealing flavor and to improve value by controlling the amount of active ingredients. The most widely-used emulsions are non-ionic because they have low toxicity, but cationic emulsions are also used in some products because of their antimicrobial properties. Emulsions are also used in making many hair and skin products, such as various types of oils and waxes.

Objective Type Questions of Colloids and Emulsions in Pharmacy
1.    An emulsion is a ......................of two immiscible liquid phases, one of which is dispersed as fine globules throughout the other.                                                
-----------------
2.    Basically emulsion may is thermodynamically................................ System of at least two immiscible liquid phases.        

a) stable ,           
b) turbid         
c) clear         
d) unstable               
-----------------
3.    The stability of the emulsion is measured in terms of the quantity of the ............................... agent used.           

a) binding agent         
b) suspending agent          
c) emulsifying agent  
d)  both a& b                             
-----------------
4.    The liquid phase in the form of  globules is called as.................................
------------------
5.    The liquid bearing the globules of the other phase is called as :

a) fluorescent phase       
b) saturated layer          
c) fatty layer         
d) continuous phase                
------------------
6.    Dispersed phase can consist of the ..............................    

a) stable liq.       
b) mobile liq       
c) semisolids 
d) plasma          
e) both b&c                      
------------------
7.    The most important example of the emulsion that is therapeutically active:

a) lotions      
b) creams
c) ointments  
d) both a & c                                
------------------
8.    In emulsions ,the particle size ranges:         

a) 0.5 - 1 mm           
b) 0.1 - 4         
c) 0.1 - 10mm          
d) 0.1 -10 micrometers                            
------------------
9.    In the preparation of the emulsions ,the most important and most frequently used phase is :

a) alkenes      
b) ether         
c) chloroform      
d) water 
e) alcohols               
-------------------
10.    In o/w emulsion, can the globules of the dispersed phase show fluorescence?       

a) yes     
b) no                
-------------------
11.    In o/w emulsions the continuous phase is ..............................                      
-------------------
12.    Milk is an important example of the................................ emulsion               
-------------------
13.    Egg yolk is an important example of...................       emulsion                     
-------------------
14.    In water in oil emulsions ,the globules contain .....................                     
--------------------
15.    Following is the important w/o emulsion used most frequently :

a) rubber latex     
b) vanishing cream   
c) oily calamine lotion
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Answers to Objective Type Questions of Colloids and Emulsions in Pharmacy 
1. system
2. d
3. c
4. dispersed phase
5. d
6. e
7. c
8. d
9. d
10. a
11. water
12. o/w
13. o/w
14. water
15. c

(These Objective Type Questions are helpful for the preparation of Pharmacy Exams)
-------------------------
Further Reading:
Tutorial pharmacy



Colloids and Emulsions

Objective Type Questions from Colloids and Emulsions in Pharmacy
16.    An emulsion in which water globules are dispersed within the oil globules so that the system may be designated as ..................................                                
--------------------
17.    medically used emulsions for oral administration are usually ...............type:

a)o/w        
b) w/o 
c) w/o/w        
d) o/w/o                             
--------------------
18.    The surface active agents used in multiple emulsions are:

a) non-ionic  
b) synthetic      
c) ionic    
d) natural      
e ) a&b   
f) c&d                             
---------------------
19.    Gelatin and Tragacanth are :

a) emulsifying agents    
b) surface active agents  
c) synthetic non-ionic     
d) b&c       
e) a&c                             
----------------------
20.    W/O  emulsions are used almost exclusively for....................... applications :

a) internal      
b) external       
c) causal                      
---------------------
21.    Calcium palmitate , spans , cholesterol and wool fat  are emulsifiers used in the preparation of :       

a) w/o  
b) o/w 
c) w/o/w      
d) o/w/o                            
---------------------
22.    Dye solubility test is mostly used for ..................of the emulsion type.  
----------------------
23.    Mostly used dye in the dye solubility test is .......................................                 
----------------------
24.    At commercial level,………………………..is used for dilution method of determination of the emulsion thpe.        

a) ether   
b) alcohol       
c) water     
d) choloroform                   
----------------------
25.    During conduction method ,the electrical circut completes when continuous phase is ......................                     
----------------------
26.    Co lour of the o/w  emulsion is usually...................................             
----------------------
27.    Initially o/w emusion feels ................................on the skin.                  
----------------------
28.    When we add oil soluble dye in the o/w emulsion, the colored phase will be ……………….                       
----------------------
29.    The British chemist Thomas Graham applied the term “colloid” to : 

a)polypeptides  
b) polysaccharides
c) flavones   
d) a&b                               
-----------------------
30.    Colloidal dispersions are distinguished form the solutions and coarse dispersions on the basis of the :

a) viscosity   
b) density    
c) particle size                            
-----------------------
31.    Most of the pharmaceutical systems are prepared in the form of the :

a) hydrophilic colloidal system       
b) lipophilic colloidal system                         
-----------------------
32.    Radioactive colloids are being used as diagnostic & ……………….. Purposes in nuclear medicines.                         
-----------------------
33.    micelles, microemulsions,liposomes, parenteral emulsions ,micro spheres ,nanoparticles are known as ……………………
------------------------------
Answers to Objective Type Questions from Colloids and Emulsions in Pharmacy 
16. w/o/w
17. a
18. e
19. d
20. b
21. a
22. determination
23. methylene-blue
24. c
25. water
26. milky white
27. non-greasy
28. dispersed phase
29. d
30. c
31. a
32. therapeutic
33. Colloidal drug delivery systems

Friday, May 7, 2010

IV admixtures

Multiple Choice Questions (MCQs) from IV admixtures in Pharmaceutics
1:  --------------------  is the preparation of pharmaceutical product that requires the measured additive of medication to a 50ml or larger bag or bottle of IV fluid.

a)    Admixture
b)    Suspension
c)    IV admixture
d)    Emulsion
-----------------
2:  The drug added to an IV solution is called -------------------- .

a)    Excipients
b)    Sodium chloride
c)    Dextrose
d)    Additive
----------------
3:  All different types of parenteral drug delivery systems are true EXCEPT--------------

a)    Decrease the safety of parenteral medications.
b)    Patient controlled analgesia
c)    Home IV therapy
d)    Home TPN
--------------
4:  Any solution administered to the patient`s veins must be -----------------

a)    Non-sterile
b)    Sterile & Pyrogen free
c)    Endotoxins
d)    Irritating
--------------
5:  Intravenous admixtures are ----------------- to which one or more additional drugs or solutions have been added.

a)    Mixtures
b)    Suspension
c)    Small volume parenteral
d)    Large volume parenteral (LVP)
---------------
6:  The intravenous admixture product should be --------------------

a)    Free of contamination (Particles, bacteria,extraneous material)
b)    The solution should be clear (All medications should be completely dissolved)
c)    Both a & b
d)    None of above.
----------------
7:  The ------------------  route is most dangerous route of administration because it by passes all of body`s natural barriers.

a)    Intra-muscular
b)    Intra-occular
c)    Both a & b
d)    Intra-venous
----------------
8:  An improperly prepared solution when administered can have very serious consequences like ----------------------

a)    Infections
b)    Emboli
c)    Occlusions
d)    All of above

-----------------
Answers to Multiple Choice Questions (MCQs) from IV admixtures in Pharmaceutics

1. c) IV admixture
2. d) Additive
3. a) Decrease the safety of parenteral medications.
4. b) Sterile & pyrogen free
5. d) Large volume parenteral (LVP)
6. c) Both a & b
7. d) Intra-venous
8. d) All of above

(These MCQs are helpful for the preparation of Pharmacy Exams)
-----------------------
Further Reading:




Capsules

In the manufacture of pharmaceuticals, encapsulation refers to a range of techniques used to enclose medicines in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally or be used as suppositories. The two main types of capsules are:
  • Hard-shelled capsules, which are normally used for dry, powdered ingredients or miniature pellets (also called spheroids that are made by the process of Extrusion and Spheronization - Spheronization is a trade mark of Caleva Process Solutions) or tablets;
  • Soft-shelled capsules, primarily used for oils and for active ingredients that are dissolved or suspended in oil.
Both of these classes of capsules are made from aqueous solutions of gelling agents like:
  • Animal protein mainly gelatin;
  • Plant polysaccharides or their derivatives like carrageenans and modified forms of starch and cellulose.
Other ingredients can be added to the gelling agent solution like plasticizers such as glycerin and/or sorbitol to decrease the capsule's hardness, coloring agents, preservatives, disintegrants, lubricants and surface treatment.
Since their inception, capsules have been viewed by consumers as the most efficient method of taking medication. For this reason, producers of drugs such as OTC analgesics wanting to emphasize the strength of their product developed the "caplet" or "capsule-shaped tablet" in order to tie this positive association to more efficiently-produced tablet pills. After the 1982 Tylenol tampering murders, capsules experienced a minor fall in popularity as tablets were seen as more resistant to tampering.

 Single piece gel encapsulation:
In 1834, Mothes and Dublanc were granted a patent for a method to produce a single-piece gelatin capsule that was sealed with a drop of gelatin solution. They used individual iron moulds for their process, filling the capsules individually with a medicine dropper. Later on, methods were developed that used sets of plates with pockets to form the capsules. Although some companies still use this method, the equipment is not produced commercially any more. All modern soft-gel encapsulation uses variations of a process developed by R.P. Scherer in 1933. His innovation was to use a rotary die to produce the capsules, with the filling taking place by blow molding. This method reduced wastage, and was the first process to yield capsules with highly repeatable dosage.
The current owner of the RPScherer technology is Catalent Pharma Solutions, the world's largest manufacturer of prescription pharmaceutical softgels.
Softgels can be an effective delivery system for oral drugs, especially poorly soluble drugs. This is because the fill can contain liquid ingredients that help increase solubility or permeability of the drug across the membranes in the body. Liquid ingredients are difficult to include in any other solid dosage form such as a tablet. Softgels are also highly suited to potent drugs (for example, where the dose is <100 ug), where the highly reproducible filling process helps ensure each softgel has the same drug content, and because the operators are not exposed to any drug dust during the manufacturing process.
In 1949, the Lederle Laboratories division of the American Cyanamid Company developed the "Accogel" process, allowing powders to be accurately filled into soft gelatin capsules.

Two piece gel encapsulation:
James Murdock of London patented the two-piece telescoping gelatin capsule in 1847. The capsules are made in two parts by dipping metal rods in the gelling agent solution. The capsules are supplied as closed units to the pharmaceutical manufacturer. Before use, the two halves are separated, the capsule is filled with powder or mor normallt spheroids made by the process of spheronization (either by placing a compressed slug of powder into one half of the capsule, or by filling one half of the capsule with loose powder) and the other half of the capsule is pressed on. With the compressed slug method, weight varies less between capsules. However, the machinery required to manufacture them is more complex.
The powder or spheroids inside the capsule contains the active ingredient(s) and any excipients, such as binders, disintegrants, fillers, glidant, and preservatives.

Osmotic-controlled Release Oral delivery System (OROS):
OROS is a controlled release oral drug delivery system in the form of a consumable capsule. The capsule has a rigid water-permeable jacket with one or more small holes. As the capsule passes through the body, the osmotic pressure of water entering the capsule pushes the active drug through the opening in the capsule.
OROS is a trademarked name owned by Alza Corporation.
Multiple Choice Questions (MCQs) from Capsules in Pharmaceutics
1-  Capsule are dosage form contain ______ of drug.

a) single dosage  
b) unit dosage    
c) double dosage   
d) both b & c
---------------
2-  Basic empty capsule shell are made from a mixture of ______.

a) sugar   
b) water  
c) Galeton 
d) all of above
---------------
3-  Galeton is ______ in air when dry.

a) Unstable  
b) stable   
c) both a & b  
d) none of above
---------------
4-  Soft Galeton capsule have ______ moisture content then hard Galeton capsule.

a) low  
b) equal  
c) high   
d)  none of above
---------------
5-  The normal shell contain _____ of moisture.

a) 9-12%  
b) 15-18%  
c) 12-15%      
d) none of above
---------------
6-  Capsule are _____ to swallowed.

a) very difficult     
b) difficult    
c) both a & b   
d) easy
----------------
7-  On large scale soft Galeton capsule are prepared by_______.

a) plate process    
b) rotator die process  
c) both a & b    
d) none of above
-----------------
8-  The hard Galeton capsule are produced by mechanical dipping of _______ of desire able shape and diameter.

a) pins    
b) pegs     
c) both a & b      
d) none of above
------------------
9-  Hard Galeton capsule contain ______ of moisture.

a) 9-12%  
b) 15-18%  
c) 12-15%      
d) none of above
------------------
10-  Capsule are should be stored at ____ and ____ humidity level.

a) dry , low   
b) dry , high   
c) cool , high   
d) cool , low
------------------
11-  Examples  of drug dispensed in soft Galeton capsule are ¬¬¬¬¬_______.

a) volatile drug  
b) liquid , suspension , powders e.t.c    
c) vitamin E , digoxin e.t.c   
d) all of above
------------------
Answers to Multiple Choice Questions (MCQs) from Capsules in Pharmaceutics
•    1- b
•    2- d
•    3- b
•    4- c
•    5- c
•    6- d
•    7- c
•    8- c
•    9- a
•    10- d
•    11- c

(These MCQs are helpful for the preparation of Pharmacy Exams)
--------------------
Further Reading: