Evolutionary operations in Optimization

Evolutionary operations is also referred to "EVOP" and is well suited for the production side of the industry.

In this prcoess, constant repetition and careful planning of the production process such as formulation is used to move towards better processes.

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

Paste, Poultice, Plaster and Suppository

Q: What do you mean by paste?
Ans: These are preparations having finely dispersed solids in the preparation.

Q: What do you mean by poultice?
Ans: These are slightly wet substances for application on the injury. These are composed of hydrophilic substances or basis having the ability of retention of heat containing solid or liquid active substances.

Q: What do you mean by medicated plaster?
Ans: These are preparations having one or more active substances. These are made in such a way that they remain in close contact with the skin at body temperature, so that the active substances can be absorbed slowly and easily through the skin or protect the skin from external environment.

Q: What do you mean by suppository?
Ans: It represents the small solid which is dissolvable at body temperature. It is usually in the form of cone or cylinder. It is usually inserted into the rectum, vagina (suppositories for vaginal insertion are called as pessaries) or urethra, nostrils or ears (Suppositories for insertion into urethra, ears or nostrils are called as bougies).
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Books reading:
The Immortal Life of Henrietta Lacks

New Atkins for a New You: The Ultimate Diet for Shedding Weight and Feeling Great.

The Other Brain: From Dementia to Schizophrenia, How New Discoveries about the Brain Are Revolutionizing Medicine and Science

Brain Rules: 12 Principles for Surviving and Thriving at Work, Home, and School

Galenical Preparation and Concoctions

Q: What do you mean by Galenical preparation?
Ans: A medicinal preparation containing one or several active plant ingredients and produce so that inert constituents and other undesirable content of the plant remain undissolved.
 
Q: How the galenical preparations are characterized?
Ans: The galenical preparations are characterized by an improved and enhanced release of the active principle and a higher efficiency.
 
Q: What galenical preparation contains?
Ans: The galenical preparation contain various herbal and chemical concoctions with varying degree of dosing strength and dosage form.
 
Q: What galenical preparation comprise for oral application?
Ans: The preparation for oral application comprise a coating resistant to gastric juice and a core comprise of an ergot alkaloid and of a sterile ester.
 
Q: What is the composition of galenical preparation?
Ans: The galenical preparation composed mainly of herbal or vegetable matter.
 
Q: What do you mean by concoctions?
Ans: It means to make something by combining or mixing different ingredients in a new way.

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Further Reading:
The Immortal Life of Henrietta Lacks

The Other Brain: From Dementia to Schizophrenia, How New Discoveries about the Brain Are Revolutionizing Medicine and Science

A Short History of Nearly Everything

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 = [[HA_organic]]²/[[HA_aqueous]]

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 D_U = 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
D_Am = 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 being a constant it becomes = 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