רגונס חפצי2005

'סמסטר ב

Reactor with Steam Condenser

2

Sulfa :G6PD -רגישות ל. 2

Pharmaceutial Manufacturing Performance

ACTIVE FORMULN FILL PACK

ACTIVE FORMULN FILL PACK

ACTIVE FORMULN FILL PACK

RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE COST

QUALITY

TIME

SAFETY

Environmental and Social Considerations

Milling & Sieving process in the pharmaceutical industry

Is used for:

Actual sizing

Changing the grain size/grain surface distribution

Density and improving mixing properties.

Variants of mills are available but each type selected depends on the consistency of the raw material while considering the requirements of the finished product.

Particle Size Distribution

Influences of Particle Size

Particle size influences dissolution

Small particles dissolve more rapidly than large ones, which is

important not only in determining the behavior of the drug in vivo

but also in various manufacturing processes.

Particle size influences flow properties of powders

The flow properties of powders are strongly dependent on particle

size and, in particular, particle shape. Since most powders are

moved from one place to another by flowing, control of flow behavior

is highly important. Generally, spherical particles flow much more

easily than elongated particles.

Particle size influences stability of dispersions

The stability of dispersions, such as suspensions and emulsions,

depends on the size of the dispersed material. The forces between

colloidal particles depend on their dimensions, and the settling.

Influences of Particle Size

Effectiveness of drug delivery by Inhalation

Our respiratory systems are incredibly efficient at filtering out particles above a certain

size. Orally or nasally inhaled drug manufacturers must ensure the product is capable of

penetrating the lungs; conversely, cleaning product manufacturers may need to provide

extra controls in order to prevent inhalation if particles are of a dangerous size.

Both tablets and capsules are produced using equipment which controls the mass of

drug and other particles by volumetric filling. Therfore any interference with the

uniformity of fill volumes may alter the mass of drug incorporated into the tables or

capsules. Thus reduce the uniformity of the medicine.

Product appearance

Particle Size Distribution

Particle Size Distribution

The particle size distribution (PSD) may be defined as

“Particle size distribution (PSD) of a powder, or granular material,

or particles dispersed in fluid, is a list of values or a mathematical

function that defines the relative amounts of particles present,

sorted according to size.”

Particle size distribution is also known as grain size distribution.

Particle Size Distribution

Significance of Particle Size Distribution (PSD)

The PSD of a material can be important in understanding its

physical and chemical properties.

It affects the reactivity of solids participating in chemical

reactions, and needs to be tightly controlled in many industrial

products.

So, What is Particle Size?

“Surprisingly, it is not a question that can be easily answered. This is because in the real world, depending upon the material properties, conditions of manufacture and storage, three distinct species will always exist in any powder, wet or dry”.

Particle Size Distribution: Measurement Techniques

There is a wide range of instrumental and other methods of

particle size analysis available. Some of the more common

methods are:

1. Sieve Analysis

2. Sedimentation Methods

3. Elutriation Techniques

4. Microscopic Sizing and Image Analysis

5. Electrical Impedance Method

6. Laser Diffraction Methods

תרופות יכולות להיות:

אבקה או משחה, טבליה: מוצקבמצב.

תמיסה או תרחיף, נוזל טהור: במצב נוזלי.

גז טהור או תערובת גזים: במצב גזי .

Size Reduction

• Raw materials often occur in sizes that are too large to be used and, therefore, they must be reduced in size. This size-reduction mechanical operation can be divided into two major categories depending on whether the material is a solid or a liquid:

• If it is solid, the operations are called grinding and

cutting. • If it is liquid, emulsification or atomization. • All depend on the reaction to shearing forces within

solids and liquids

Size Reduction:

Reduces large solid particles to smaller particles by mechanical means.

Factors affecting size reduction

1. Hardness

2. Stickiness

3. Abrasiveness

4. Temperature

5. Material Structure

6. Moisture Content

7. Physiological Effect

8. Purity Required

9. Ratio of Feed Size to Product Size

SIZE REDUCTION METHODS

There are many different types of size reduction method employed. 1.Cutting methods: used to break down large pieces The material is cut by means of a sharp blade or blades.

2. Compression methods: The material is crushed by application of pressure.

3. A ball mill , fluid energy mills and pin mills are examples of a comminuting method which produces size reduction by both impact and attrition of particles

SIZE REDUCTION METHODS

Three basic mill components:

•All milling equipment have three basic components: 1. A structure for feeding material to the mill. 2. The milling chamber and its working parts. 3. A receiver or collector in which the milled product is deposited

Mill chambers Pin Mill

Milling equipment – impact mills Hammer mills

Medium to coarse size reduction

Peripheral speed 20-50 m/sec

Pin mills

Peripheral speed up to 200 m/sec

Capable of fine grinding

Can be used to mill sticky materials

Ball Mill

Ball Mill - Batch type The ball mill is a cylindrical shell usually filled

to about half its volume with

grinding media (ball).

The balls may be

of metal or porcelain

Continuous ball milling • Conical shell with grinding

media of different sizes • Feed enter from the hallow

end of the mill and milled material exits through coarse screen.

• The outlet is covered with a coarse screen to prevent the loss of the balls

Grinding Ball selection In Grinding, selecting (calculate) the correct or optimum ball size that allows for the best and optimum/ideal or target grind size to be achieved by your ball mill is an important thing for a Processing Engineer

!!!Often, the ball used in ball mills is oversize “just in case”. Well, this safety factor can cost you much in recovery

Grinding Ball selection

Advantages of the ball mill

Ball milling boasts several advantages over other systems: the cost of installation, power and grinding medium is low

It is suitable for both batch and continuous operation, similarly it is suitable for open as well as closed circuit grinding

Applicable for materials of all degrees of hardness

Speed of Rotation 1. At low speeds (a): The mass of balls will slide or roll over each other and only a negligible amount of size reduction will occur. 2. At high speed (centrifugation) (c): above the critical speed the mill is said to be centrifuging and grinding of material not occur. 3. At about two-thirds of the critical speed (Optimum speed).

Milling equipment – stirred media mill

Critical parameters

Agitator speed

Feed rate

Size of beads

Bead charge

Density of beads

Design of blades

Mill chamber

Residence time

Mill selection

Wibowo and Ng (1999), AIChE Journal 45 (8) 1629-1648

Particle size reduction

Mixing is more uniform if ingredients are roughly the same size

Milling of wet granules can promote uniform and efficient drying

Increased surface area can improve dissolution rate and bioavailablity

Improved content uniformity of dosage units

Excessive heat generation can lead to degradation, change in polymorphic form

Increase in surface energy can lead to agglomeration

May result in excessive production of fines or overly broad particle size distribution

Benefits

Disadvantages

Sieving - ניפוי