Tuesday, September 7, 2010

Manufacturing

Manufacture of the tableting blend
In the tablet pressing process, the main guideline is to ensure that the appropriate amount of active ingredient is in each tablet. Hence, all the ingredients should be well-mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for compression into a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression.

Wet granulation
Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis.
Procedure
Step 1: The active ingredient and excipients are weighed and mixed.
Step 2: The wet granulate is prepared by adding the liquid binder–adhesive to the powder blend and mixing thoroughly. Examples of binders/adhesives include aqueous preparations of cornstarch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, gelatin, and povidone.
Step 3: Screening the damp mass through a mesh to form pellets or granules.
Step 4: Drying the granulation. A conventional tray-dryer or fluid-bed dryer are most commonly used.
Step 5: After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to create granules of uniform size.
Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a uniformly mixed state. High shear wet granulation processes use equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the manufacturing process. Fluid bed granulation is a multiple-step wet granulation process performed in the same vessel to pre-heat, granulate, and dry the powders. It is used because it allows close control of the granulation process.

Dry granulation
Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced. However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create yield problems for the tablet. Dry granulation requires drugs or excipients with cohesive properties, and a 'dry binder' may need to be added to the formulation to facilitate the formation of granules.

Granule lubrication
After granulation, a final lubrication step is used to ensure that the tableting blend does not stick to the equipment during the tableting process. This usually involves low shear blending of the granules with a powdered lubricant, such as magnesium stearate or stearic acid.

Manufacture of the tablets
Whatever process is used to make the tableting blend, the process of making a tablet by powder compaction is very similar. First, the powder is filled into the die from above. The mass of powder is determined by the position of the lower punch in the die, the cross-sectional area of the die, and the powder density. At this stage, adjustments to the tablet weight are normally made by repositioning the lower punch. After die filling, the upper punch is lowered into the die and the powder is uniaxially compressed to a porosity of between 5 and 20%. The compression can take place in one or two stages (main compression, and, sometimes, pre-compression or tamping) and for commercial production occurs very fast (500–50 msec per tablet). Finally, the upper punch is pulled up and out of the die (decompression), and the tablet is ejected from the die by lifting the lower punch until its upper surface is flush with the top face of the die. This process is simply repeated many times to manufacture multiple tablets.
Common problems encountered during tablet manufacturing operations include:
poor (low) weight uniformity, usually caused by uneven powder flow into the die
poor (low) content uniformity, caused by uneven distribution of the API in the tableting blend
sticking of the powder blend to the tablet tooling, due to inadequate lubrication, worn or dirty tooling, and sub-optimal material properties
capping, lamination or chipping. Such mechanical failure is due to improper formulation design or faulty equipment operation.

Tablet compaction simulator
Tablet formulations are designed and tested using a laboratory machine called a Tablet Compaction Simulator or Powder Compaction Simulator. This is a computer controlled device that can measure the punch positions, punch pressures, friction forces, die wall pressures, and sometimes the tablet internal temperature during the compaction event. Numerous experiments with small quantities of different mixtures can be performed to optimise a formulation. Mathematically corrected punch motions can be programmed to simulate any type and model of production tablet press. Initial quantities of active pharmaceutical ingredients are very expensive to produce, and using a Compaction Simulator reduces the amount of powder required for product development

Advantages and disadvantages

Tablets are simple and convenient to use. They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Colored coatings, embossed markings and printing can be used to aid tablet recognition. Manufacturing processes and techniques can provide tablets special properties, for example, sustained release or fast dissolving formulations.
Some drugs may be unsuitable for administration by the oral route. For example, protein drugs such as insulin may be denatured by stomach acids. Such drugs cannot be made into tablets. Some drugs may be deactivated by the liver when they are carried there from the gastrointestinal tract by the hepatic portal vein (the "first pass effect"), making them unsuitable for oral use. Drugs which can be taken sublingually are absorbed through the oral mucosae, so that they bypass the liver and are less susceptible to the first pass effect. The oral bioavailability of some drugs may be low due to poor absorption from the gastrointestinal tract. Such drugs may need to be given in very high doses or by injection. For drugs that need to have rapid onset, or that have severe side effects, the oral route may not be suitable. For example salbutamol, used to treat problems in the pulmonary system, can have effects on the heart and circulation if taken orally; these effects are greatly reduced by inhaling smaller doses direct to the required site of action.
Tablet properties
Tablets can be made in virtually any shape, although requirements of patients and tableting machines mean that most are round, oval or capsule shaped. More unsusual shapes have been manufactured but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems.
Tablet diameter and shape are determined by the machine tooling used to produce them - a die plus an upper and a lower punch are required. This is called a station of tooling. The thickness is determined by the amount of tablet material and the position of the punches in relation to each other during compression. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, thickness, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they don't break up in the bottle, yet friable enough that they disintegrate in the gastric tract.
Tablets need to be strong enough to resist the stresses of packaging, shipping and handling by the pharmacist and patient. The mechanical strength of tablets is assessed using a combination of (i) simple failure and erosion tests, and (ii) more sophisticated engineering tests. The simpler tests are often used for quality control purposes, whereas the more complex tests are used during the design of the formulation and manufacturing process in the research and development phase. Standards for tablet properties are published in the various international pharmacopeias (USP/NF, EP, JP, etc).
Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall.
Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules

Tablet


A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted into a solid. The excipients can include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet's appearance.
The compressed tablet is the most popular
dosage form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site; it is usually taken orally, but can be administered sublingually, buccally, rectally or intravaginally. The tablet is just one of the many forms that an oral drug can take such as syrups, elixirs, suspensions, and emulsions. Medicinal tablets were originally made in the shape of a disk of whatever color their components determined, but are now made in many shapes and colors to help distinguish different medicines. Tablets are often stamped with symbols, letters, and numbers, which enable them to be identified. Sizes of tablets to be swallowed range from a few millimeters to about a centimeter. Some tablets are in the shape of capsules, and are called "caplets". Medicinal tablets and capsules are often called pills. This is technically incorrect, since tablets are made by compression, whereas pills are ancient solid dose forms prepared by rolling a soft mass into a round shape. Other products are manufactured in the form of tablets which are designed to dissolve or disintegrate; e.g. cleaning and deodorizing products


Tabletting formulationsIn the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders can segregate during manufacturing operations due to different densities, which can result in tablets with poor drug or active pharmaceutical ingredient (API) content uniformity but granulation should prevent this. Content uniformity ensures that the same API dose is delivered with each tablet.
Some APIs may be tableted as pure substances, but this is rarely the case; most formulations include
excipients. Normally, an pharmacologically inactive ingredient (excipient) termed a binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose and modified cellulose (for example hydroxypropyl methylcellulose).
Often, an ingredient is also needed to act as a disintegrant to aid tablet dispersion once swallowed, releasing the API for absorption. Some binders, such as starch and cellulose, are also excellent disintegrants.
Small amounts of lubricants are usually added, as well. The most common of these is magnesium stearate; however, other commonly used tablet lubricants include
stearic acid (stearin), hydrogenated oil, and sodium stearyl fumarate. These help the tablets, once pressed, to be more easily ejected


Advantages and disadvantages

Tablets are simple and convenient to use. They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Colored coatings, embossed markings and printing can be used to aid tablet recognition. Manufacturing processes and techniques can provide tablets special properties, for example, sustained release or fast dissolving formulations.
Some drugs may be unsuitable for administration by the oral route. For example, protein drugs such as insulin may be denatured by stomach acids. Such drugs cannot be made into tablets. Some drugs may be deactivated by the
liver when they are carried there from the gastrointestinal tract by the hepatic portal vein (the "first pass effect"), making them unsuitable for oral use. Drugs which can be taken sublingually are absorbed through the oral mucosae, so that they bypass the liver and are less susceptible to the first pass effect. The oral bioavailability of some drugs may be low due to poor absorption from the gastrointestinal tract. Such drugs may need to be given in very high doses or by injection. For drugs that need to have rapid onset, or that have severe side effects, the oral route may not be suitable. For example salbutamol, used to treat problems in the pulmonary system, can have effects on the heart and circulation if taken orally; these effects are greatly reduced by inhaling smaller doses direct to the required site of action

Thursday, September 2, 2010

Soil mechanics


In geotechnical engineering, soils are considered a three-phase material composed of: rock or mineral particles, water and air. The voids of a soil, the spaces in between mineral particles, contain the water and air.
The engineering properties of soils are affected by four main factors: the predominant size of the mineral particles, the type of mineral particles, the grain size distribution, and the relative quantities of mineral, water and air present in the soil matrix. Fine particles (fines) are defined as particles less than 0.075 mm in diameter.

Soil properties


Main article:
Soil mechanics
Some of the important properties of soils that are used by geotechnical engineers to analyze site conditions and design earthworks, retaining structures, and foundations are [2]:
Unit Weight
Total unit weight: Cumulative weight of the solid particles, water and air in the material per unit volume. Note that the air phase is often assumed to be weightless.
Porosity
Ratio of the volume of voids (containing air, water, or other fluids) in a soil to the total volume of the soil. A porosity of 0 implies that there are no voids in the soil.
Void ratio
is the ratio of the volume of voids to the volume of solid particles in a soil. Void ratio is mathematically related to the porosity.
Permeability
A measure of the ability of water to flow through the soil, expressed in units of velocity.
Compressibility
The rate of change of volume with effective stress. If the pores are filled with water, then the water must be squeezed out of the pores to allow volumetric compression of the soil; this process is called consolidation.
Shear strength
The
shear stress that will cause shear failure.
Atterberg Limits
Liquid limit, plastic limit, and shrinkage limit. These indices are used for estimation of other engineering properties and for soil classification.

Foundation (engineering) Design


Foundations are designed to have an adequate load capacity with limited settlement by a geotechnical engineer, and the foundation itself is designed structurally by a structural engineer.

Inadequate foundations in muddy soils below sea level caused these houses in the Netherlands to subside.
The primary design concerns are
settlement and bearing capacity. When considering settlement, total settlement and differential settlement is normally considered. Differential settlement is when one part of a foundation settles more than another part. This can cause problems to the structure the foundation is supporting. It is necessary that a foundation not be loaded beyond its bearing capacity or the foundation will "fail".
Other design considerations include scour and
frost heave. Scour is when flowing water removes supporting soil from around a foundation (like a pier supporting a bridge over a river). Frost heave occurs when water in the ground freezes to form ice lenses.[citation needed]
Changes in soil moisture can cause
expansive clay to swell and shrink. This swelling can vary across the footing due to seasonal changes or the effects of vegetation removing moisture. The variation in swell can cause the soil to distort, cracking the structure over it. This is a particular problem for house footings in semi-arid climates such as South Australia, Southwestern US, Turkey, Israel, Iran and South Africa where wet winters are followed by hot dry summers. Raft slabs with inherent stiffness have been developed in Australia with capabilities to resist this movement.[citation needed]
When structures are built in areas of
permafrost, special consideration must be given to the thermal effect the structure will have on the permafrost. Generally, the structure is designed in a way that tries to prevent the permafrost from melting.[citation needed]

Foundation (engineering)

A foundation (also called a groundsill) is a structure that transfers loads to the earth. Foundations are generally broken into two categories: shallow foundations and deep foundations

Foundation types
Shallow foundation
Main article:
Shallow foundation
Shallow foundation is, usually, embedded a meter or so into soil. One common type is the spread footing which consists of strips or pads of concrete (or other materials) which extend below the frost line and transfer the weight from walls and columns to the soil or bedrock. Another common type is the slab-on-grade foundation where the weight of the building is transferred to the soil through a concrete slab placed at the surface.[citation needed]

Deep foundation
Main article:
Deep foundation
A deep foundation is used to transfer a load from a structure through an upper weak layer of soil to a stronger deeper layer of soil. There are different types of deep foundations including helical piles, impact driven piles, drilled shafts, caissons, piers, and earth stabilized columns. The naming conventions for different types of foundations vary between different engineers. Historically, piles were wood, later steel, reinforced concrete, and pre-tensioned concrete.[citation needed]

Monopile foundation
A
monopile foundation utilizes a single, generally large-diameter, foundation structural element to support all the loads (weight, wind, etc.) of a large above-surface structure.
A large number of monopile foundations
[1] have been utilized in recent years for economically constructing fixed-bottom offshore wind farms in shallow-water subsea locations.[2] For example, a single wind farm off the coast of England went online in 2008 with over 100 turbines, each mounted on a 4.7-meter-diameter monopile foundation in ocean depths up to 18 meters of water.[3] An earlier (2002) wind farm in the North Sea west of Denmark utilizes 80 large monopiles of 4 meter diameter sunk 25 meters deep into the seabed.[4]

Base-isolating foundation

Base isolator being tested at the UCSD Caltrans-SRMD facility
Main article:
Base isolation
Base-isolating foundation, also known as seismic or base isolation system, is a collection of structural elements which is intended to substantially decouple a superstructure from its substructure resting on a shaking ground thus protecting a building or non-building structure's integrity during a potentially devastating earthquake. The base-isolating system may be constructed on either a shallow foundation or a deep foundation substructure.
The base-isolating foundation design is believed to be a powerful tool of contemporary
earthquake engineering pertaining to the passive structural vibration control technologies

Retaining wall

A retaining wall is a structure designed and constructed to resist the lateral pressure of soil when there is a desired change in ground elevation that exceeds the angle of repose of the soil. The active pressure increases on the retaining wall proportionally from zero at the upper grade level to a maximum value at the lowest depth of the wall. The total pressure or thrust may be assumed to be acting through the centroid of the triangular distribution pattern, one-third above the base of the wall

Definition

Retaining walls serve to retain the lateral pressure of soil. The basement wall is thus one form of retaining wall.
However, the term is most often used to refer to a cantilever retaining wall, which is a freestanding structure without lateral support at its top.
[2]

Typically retaining walls are cantilevered from a footing extending up beyond the grade on one side and retaining a higher level grade on the opposite side. The walls must resist the lateral pressures generated by loose soils or, in some cases, water pressures. [3]
The most important consideration in proper design and installation of retaining walls is to recognize and counteract the fact that the retained material is attempting to move forward and downslope due to gravity. This creates lateral earth pressure behind the wall which depends on the angle of internal friction (phi) and the cohesive strength (c) of the retained material, as well as the direction and magnitude of movement the retaining structure undergoes.
Lateral earth pressures are typically smallest at the top of the wall and increase toward the bottom. Earth pressures will push the wall forward or overturn it if not properly addressed. Also, any
groundwater behind the wall that is not dissipated by a drainage system causes an additional horizontal hydrostatic pressure on the wall.[4]
It is very important to have proper drainage behind the wall as it is critical to the performance of retaining walls. Drainage materials will reduce or eliminate the hydrostatic pressure and will therefore greatly improve the stability of the material behind the wall, assuming that this is not a retaining wall for water.
As an example, the
International Building Code requires retaining walls to be designed to ensure stability against overturning, sliding, excessive foundation pressure and water uplift; and that they be designed for a safety factor of 1.5 against lateral sliding and overturning

Types







Gravity

Construction types of gravity retaining walls
Gravity walls depend on the weight of their mass (stone, concrete or other heavy material) to resist pressures from behind and will often have a slight
'batter' setback, to improve stability by leaning back into the retained soil. For short landscaping walls, they are often made from mortarless stone or segmental concrete units (masonry units)[6]. Dry-stacked gravity walls are somewhat flexible and do not require a rigid footing in frost areas. Home owners who build larger gravity walls that do require a rigid concrete footing can make use of the services of a professional excavator, which will make digging a trench for the base of the gravity wall much easier.
Earlier in the 20th century, taller retaining walls were often gravity walls made from large masses of concrete or stone. Today, taller retaining walls are increasingly built as composite gravity walls such as: geosynthetic or with precast facing;
gabions (stacked steel wire baskets filled with rocks); crib walls (cells built up log cabin style from precast concrete or timber and filled with soil); or soil-nailed walls (soil reinforced in place with steel and concrete rods).[7]


Cantilevered

Conterfort/Buttress on Cantilevered Wall
Cantilevered retaining walls are made from an internal stem of steel-reinforced, cast-in-place concrete or mortared masonry (often in the shape of an inverted T). These walls cantilever loads (like a
beam) to a large, structural footing, converting horizontal pressures from behind the wall to vertical pressures on the ground below. Sometimes cantilevered walls are butressed on the front, or include a counterfort on the back, to improve their strength resisting high loads. Buttresses are short wing walls at right angles to the main trend of the wall. These walls require rigid concrete footings below seasonal frost depth. This type of wall uses much less material than a traditional gravity wall.




Sheet piling

Sheet pile wall
Sheet pile retaining walls are usually used in soft soils and tight spaces. Sheet pile walls are made out of steel, vinyl or wood planks which are driven into the ground. For a quick estimate the material is usually driven 1/3 above ground, 2/3 below ground, but this may be altered depending on the environment. Taller sheet pile walls will need a tie-back anchor, or "dead-man" placed in the soil a distance behind the face of the wall, that is tied to the wall, usually by a cable or a rod. Anchors are placed behind the potential failure plane in the soil.
Anchored

See also: Tieback (geotechnical)
An anchored retaining wall can be constructed in any of the aforementioned styles but also includes additional strength using cables or other stays anchored in the rock or soil behind it. Usually driven into the material with boring, anchors are then expanded at the end of the cable, either by mechanical means or often by injecting pressurized concrete, which expands to form a bulb in the soil. Technically complex, this method is very useful where high loads are expected, or where the wall itself has to be slender and would otherwise be too weak.
Alternative Retaining Techniques

Soil nailing

Main article: Soil nailing
Soil nailing is a technique in which soil slopes, excavations or retaining walls are reinforced by the insertion of relatively slender elements - normally steel reinforcing bars. The bars are usually installed into a pre-drilled hole and then grouted into place or drilled and grouted simultaneously. They are usually installed untensioned at a slight downward inclination. A rigid or flexible facing (often sprayed concrete) or isolated soil nail heads may be used at the surface.
Soil-strengthened

a number of systems exist that do not simply consist of the wall itself, but reduce the earth pressure acting on the wall itself. These are usually used in combination with one of the other wall types, though some may only use it as facing (i.e. for visual purposes).
Gabion meshes

Main article:
Gabion
This type of soil strengthening, often also used without an outside wall, consists of wire mesh 'boxes' into which roughly cut stone or other material is filled. The mesh cages reduce some internal movement/forces, and also reduce erosive forces.
Mechanical stabilization

Main article:
Mechanically stabilized earth
Mechanically stabilized earth, also called MSE, is soil constructed with artificial reinforcing via layered horizontal mats (geosynthetics) fixed at their ends. These mats provide added internal shear resistance beyond that of simple gravity wall structures. Other options include steel straps, also layered. This type of soil strengthening usually needs outer facing walls (S.R.W.'s - Segmental Retaining Walls) to affix the layers to and vice versa. [1]
The wall face is often of precast concrete units[6] that can tolerate some differential movement. The reinforced soil's mass, along with the facing, then acts as an improved gravity wall. The reinforced mass must be built large enough to retain the pressures from the soil behind it. Gravity walls usually must be a minimum of 50 to 60 percent as deep or thick as the height of the wall, and may have to be larger if there is a slope or surcharge on the wall