Statistical Quality Control in Pharmaceutics

Definition:

Statistical quality control (SQC)is defined as:
“The monitoring of quality by application of statistical method in all stages of production.”

Explanation:
Statistical methods of investigation are based on the theory of probability.

It relates to the characteristic of product from both qualitative and quantitative point of views to meet the established standards.

Uses:

It has been used to serve:

• As a basis for improved evaluation of materials through more representative sampling technique

• As a means of achieving sharper control in certain manufacturing processes

• To provide logical approach to variations

Selection:

Selection of appropriate method depends on:
• Type of measurement
• Sampling techniques
• Design of Experiments
• Type of Sample distribution

Procedure:

The procedure consists of:

• Proper sampling of product
• Determining quality variations of the sample
• Making inferences to the entire batch under investigation from the observed data
• Once the characteristic data pattern of a process has been determined, the pattern can be utilized to predict the limits within which future data can be expected to fall as a matter of chance, and to determine when significant variations in the process have taken place.

Data Analysis:
Data can be analyzed by using appropriate method of analysis:

t-test:
t-test for comparison of two populations. T-value is calculated and from t-value the P-value is noted from the table:

If
P>0.05; test is non-significant

And if
P<0.05; test is significant.

ANOVA:
It means analysis of variance and is used for comparison of more than 2 parameters.

Objectives:
The objective is to determine whether the major source of observed variations is by chance or assignable.

Types of variations:

Chance variations:
These variations are inevitable because any program of production and inspection has its own unique chance causes of variations which can not be controlled or eliminated and often cannot be identified.

Assignable variations:
These variations can usually be detected and corrected by statistical techniques. Assignable variations are usually caused by machine or a specific batch of production or a container.

Thus the use of SQC permits the:
• Evaluation of magnitude of chance variation of product quality.
• Detection of assignable variations of product quality by means of QC charts.

Sublimation

Definition:
It is conversion of a substance in solid state to a gaseous state, which is not accompanied by the formation of liquid phase.

It is similar in some aspects to the distillation process.

Process of sublimation:
At normal pressures, most of the chemical substances either compounds or elements have three different states of matter at various temperatures. In these circumstances, change from solid state to gaseous state requires a median state that is liquid.

On the other hand, some of the chemical substances such as compounds and elements at certain pressures go directly from solid state to the gaseous state. This occurs when the atmospheric pressure applied on the material is very less to inhibit the molecules from going out of the solid state i.e. a substance go through the process of sublimation only if the vapor pressure is less than that of the triple point for that substance.

Triple point:
The triple point is the point possessing a fixed pressure and temperature at which the solid, liquid and gaseous phases of a material are able to co-exist independently.

If the vapor pressure over the solid substance is more than that of the triple point, the solid will convert to vapor after passage through the liquid phase. The following phase diagram will help to understand the triple point.

Line OA:
In this diagram, line OA shows the melting points of the solid substance at different pressures. In this line, left side shows the existence of solid form while the right side shows the existence of liquid form. This line shows the points of co-existence of the solid and the liquid.

Line OB:
The line OB shows the vapor-pressure curve of the liquid at different temperatures. Above this line liquid phase exists and below this line vapor phase of the substance exists. This line shows the points of co-existence of the liquid and the vapors.

Line OC:
The line OC shows the sublimation curve of the solid. This line shows the points of co-existence of the solid and the vapors at different states of temperatures and pressure.

Point O:
In this diagram, the point O represents the triple point.

Enthalpy:
Enthalpy of sublimation is equal to the sum of enthalpy of fusion and enthalpy of vaporization.

Sublimation process represents an endothermic phase transition as shown by the phase diagram.

Examples:
Nearly all of the solids have some tendency of conversion from solid to gaseous state at a particular temperature and pressure.

Elements:
Cadmium, Zinc, Arsenic, Carbon

Compounds:
CO2 (Dry ice), NH4Cl

Uses:
Its most important use is in freeze-drying.

Elutriation

The word “Elutriation” is derived from the Latin word “elutriare” meaning “to wash out”.

Definition:
It is the separation, purification or removal of something from a mixture by decanting, straining or washing.

Process of elutriation:
In the process of elutriation, the movement of the fluid, generally water or air, is in the opposite direction to that of the sedimentation process.

Types of elutriation:
According to direction:

Vertical elutriation:
In the gravitational process, the larger particles present in water (or any other liquid) will move vertically downwards with the affect of gravity while the small particles in the fluid travels straight up with the fluid. This is a type of vertical elutriation.

Horizontal elutriation:
If a water current of suspended particles is flowed through a settling chamber. The particles that move out of the water current are collected in the bottom of the chamber. This is a type of horizontal elutriation.

Centrifugal elutriation:
In this case the water current is caused to spin with some force resulting in the large centrifugal force on the suspended particles. The heavier particles will settle to the walls of the elutriator or to the bottom.

The DorrClone is an example of a centrifugal-type of classifier.

According to the type of fluid:

• Air elutriation

• Water elutriation

If the velocity of the fluid is smaller than the velocity of setting down of the particles then the particles will settle downwards. On the other hand, if the velocity of the fluid is larger than the velocity of setting down of the particles then the particles will be carried up along with the fluid.

Air elutriation will give precise separation of the particles and in less time than water elutriation.

Factors affecting elutriation:

Elutriation is affected by the

• velocity of the fluid

• the particle size : As the small sized particles will flow (upward) along the fluid while the large sized particles will move downwards (against the velocity of the fluid).

• position of the particle in the (tube containing) fluid

• density of the particle

In a tube, there exist different velocities i.e. the velocity is largest in the centre and is smallest along the walls of the tube. So the small sized particles move upward, when in the centre and in the meantime they are also pushed towards the wall of the tube. Where the velocity is smaller and here the small sized particles start to move downwards.

Process of removal of particles:

If the upward flow of the water (or any other liquid) is slightly increased, the small sized particles (which move down slowly) will move along the movement of the water (i.e. upward) and will be removed from the water. In this process, the medium sized particles will remain immobile and the heavier particles will continue to move downward.

The upward flow of water will then again be increased and the next smallest size particles will be removed. And in this way, particles of different sizes will be separated and obtained.

Centrifugation

It refers to the process of sedimentation by using centrifuge machine.

Basic idea behind centrifugation:
Centrifugation is based on the widely known idea of sedimentation by the use of centrifugal force, which represents a force that apparently moves a spinning or rotating object away from the axis of rotation in a curved path.

Centrifugal effect:
The processes using centrifugal force (F) can be described by the equations involving the gravitational constant (G). In this case, it is easy to determine the centrifugal force in the terms of the ratio of the centrifugal force to the gravitational force. In addition, this ratio represents the centrifugal effect (C).

Centrifugal effect (C) shows that how many times the centrifugal force is larger than gravitational force.

C = 2.013 dn^2

Where
d = diameter of rotation
n = speed of rotation

Here in this equation, “n” has the value in “s-1” and “d” has the value in “m”.


This equation shows that centrifugal effect is directly proportional to the diameter and to the square of the speed of the rotation i.e. greater will be the diameter of the tube or container more will be centrifugation and similarly for the speed of rotation.

Factors affecting centrifugation:

Centrifugation is basically affected by centrifugal effect. Moreover, nature of the liquid medium in which the particles are placed also affects the centrifugation.

Apparatus for centrifugation (Centrifuges):
Container is the most important part of centrifugation apparatus i.e. centrifuges. This container is used for the placement of a mixture or solution of solid and liquid or of a solution of two liquids.

This container is then rotated at greater speed resulting in the separation of the ingredients of the mixture takes place by the use of centrifugal force.

Mechanism for the separation in the apparatus of centrifugation:
A mixture of liquid or solid in a liquid of low density can be separated as the material of larger density is thrown in the outward direction to the bottom of the tube or container with a larger force. This results in the separation of pure, low-density liquid as a transparent or purified supernatant liquid which forms upper layer.

Types of centrifuges:

There are two basic types of centrifuges:

1. Sedimentation

2. Filtration

Sedimentation centrifuges:

The basic principle, in the sedimentation type of centrifuges, is difference in the densities of the ingredients of the mixture. In these types of centrifuges, the particles are settled to the wall by the action of the centrifugal force.

These types of centrifuges are used for the separation of ingredients of the mixture of solid in liquid as well as liquid in liquid.

Two types of centrifuges are based on the principle of sedimentation:

1. Bottle centrifuge

2. Disc type centrifuge

Bottle centrifuge:
It is mostly used centrifuge machine in the laboratories. It consists of a vertical rotating rod that causes the “bottle-type” containers or test tubes, which are fixed symmetrically, to be rotated in a horizontal plane resulting in the separation of the materials of varying densities. The vertical rod is rotated usually by means of electric motor. Sometimes, gas turbines can also be used for the rotation.

Disk type centrifuge:
It consists of vertical pile of thin conical disks, which are arranged in the manner of one on the top of another. The sedimentation of the particles takes place in the space between neighbouring cones. In this way, settling distance is greatly reduced, thereby increasing the rate at which the particles in the material are separated. The cones are adjusted in such a manner that heavier material moves down the surface easily upon reaching the inner surface of the cone.

Filtration centrifuges:

These types of centrifuges are used for the separation of the mixture of solid in liquid only performing the operation similar to the filtration process. These are also sometimes referred to as clarifiers.

It is same in the basic operation to the sedimentation types of centrifuges but instead of solid containers or tubes, it contains a porous wall or perforated containers or baskets, which causes the liquid phase to pass through it but keeps the solid phase on it.

Centrifuge based on the principle of filtration is “Basket centrifuge”.

Basket centrifuge:
Basket centrifuge consists of a porous wall and rotor which is cylindrical and tubular in structure. The porous wall is some times replaced by one or more of the fine mesh screens. The fluid go through the screen where as the particles larger in size are left on the screen.

Application of centrifugation:

Centrifugation is used for the separation of ingredients of a mixture of solid in liquid or liquid in liquid as the degree of separation achieved by centrifugation is of greater amplitude than the action due to gravity.

It is important specifically when the separation by normal filtration methods is difficult such as in the separation of fluids of highly viscous nature.

In the pharmaceutical research, it is considered as an important tool in determining the stability of emulsions.

Bottle centrifuge can be used for:

1. Finding the sediments present in crude vegetable and mineral oils
2. Determination of the butterfat content in the milk
3. Various clinical trials and tests

Disk type centrifuge can be used for refining of vegetable oils by removing soap stock

Basket centrifuge can be used for:

1. Drying and washing of several different kinds of crystals and fibrous materials
2. The preparation of cane sugar.

Bougies

Introduction:
Its name came from the town namely “bougie” in Algeria, which was famous for trading in wax. Its original meaning is “A candle made by wax”. These are the types of suppositories intended for insertion into the urethra, nostrils or ears.

It is also a medical instrument in the shape of cylinder, made up of a flexible tube.

Forms of bougie:
Bulbous bougie:
It is a form of bougie with a bulb shaped tip.

Eder-pustow bougie:
It is a form of metal bougie which resembles olive in shape. It may be used in esophageal stricture.

Elastic bougie:
A bougie made of rubber or latex.

Elbowed bougie:
A bougie with a bent near its tip.

Use:
It is used for opening of constricted areas in tubular organs such as urethra or esophagus and rectum, so, that medicines for local application or another instruments can easily be inserted in that part.

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

Hydryllin syrup

Hydryllin syrup is used for cough. It is a product of Searle Pharmaceuticals.

Ingredients:
Its active ingredients are

1. Aminophylline (It is a bronchodilator i.e. eases breathing by opening the air passages to the lungs)
2. Ammonium chloride (It is an expectorant i.e. produces and getting rid of thick mucus in the respiratory passages)
3. Diphenhydramine (An antihistamine to treat allergies)
4. Menthol (Mint tasting compound obtained from peppermint oil)

Uses:
Cough Expectorant

Contraindications:
It is contra-indicated in patients of acute myocardial infarction or peptic ulcers.
It is also contra-indicated in patients who are hypersensitive to its components.

List of Cough Syrups from multi-national companies available in Pakistan:
1. Actifed DM Cough syrup (GSK)
2. Babynol Cough Syrup (Woodwards)
3. Benatuss Syrup (Johnson)
4. Benylin DM Syrup (Johnson)
5. Benylin E Syrup (Johnson)
6. Corex D Cough Syrup (Pfizer)
7. Cosome Cough Syrup (Merck)
8. Cosome E Cough Syrup (Merck)
9. Daycor Syrup (Abbott)
10. Nicor Syrup (Abbott)
11. Phensedyl-P syrup (Sanofi Aventis)
12. Rondec Cough Syrup (Abbott)
13. Rondec-C Cough Syrup (Abbott)
14. Sancos Syrup (Novartis)
15. Triaminic Cough Syrup (Novartis)
16. Tussivil Syrup (Pfizer)