LIQUID SECTION

 Liquid Section

Syrup and suspension have used as the oral administration, as the dose of liquid medicine in earlier. In the modem century, the therapeutic use of syrup and suspension is modernized by the discovery of new therapeutic agents with the help of chemistry.

 Syrup

Syrup is the concentrated aqua solution of sucrose and other sugars or sweetening agents to which small quantities of suitable polyhydric alcohols may be added to retard crystallization or to increase the solubility of the other ingredients. It usually contains aromatic or other flavoring materials. It should keep in well-closed containers and stored at temperatures not exceeding 90°c.

 Manufacturing of syrup

To solve the formulation problems encountered with pharmaceutical liquid, an interesting dichotomy of investigate skills is required. On the one hand, solubility and stability factors can be approached with the precision long associated with the exact science; on the other hand, flavoring and other organoleptic characteristics remain subjective factors for which the application of the scientific method still plays a distressingly minor role. Thus, the successful formulation of liquids as well as other dosage forms requires a blend of scientific acuity and pharmaceutical art.

Quality Control of Syrup

Whether or not a substance dissolves in a given system and the extent to which it dissolves depends largely on nature and intensity of the forces presents in the interaction energies and the interplay of electronic and steric factors in determining the solubility of substances in various classes of solvents. The solubility is the factors of the following important terms:

A. pH

The solubility of a large number of modem chemotherapeutic agents can be marketedly influenced by the pH of their environment. The pH that satisfies the solubility requirements, mast not conflict with product requirements, such as stability and physiological compatibility. In addition to this if pH is critical to maintaining drug solubility; the system must be adequately buffered. The selection of a buffer must be consistent with the following criteria:

1. The buffer must have adequate capacity in the desired pH range

2. The buffer must be biologically safe for the intended use

3. The buffer should have little or no deleterieres effect on the stability of the final product

4. The buffer should permit acceptable flavoring and coloring agents

B. Co solvency

Weak electrolytes and monopolar molecules frequently have poor water solubility. Their solubility usually can be increased by the addition of water-miscible solvent in which the drug has good solubility. This process is known as Co solvency.

C. Dielectric constant

A more practical approach to the solubility problem may be found in what has come to be known as the dielectric requirement. According to this theory every solute shows a maximum solubility in any given solvent system at one or more specific dielectric constants. The absolute solubility of a solute may vary considerably in two different solvents of the same dielectric constant, but the solubility profile, as a function of dielectric constants appears to be similar for a solute in a wide variety of solvent systems.

D. Hydrotropy

The term hydtropy has been used to designate the increased in solubility in water of various substances due to the presence of large amount of additives. The mechanism by which this effect occurs is not clear. Some workers have speculated that hydrotropy is simply another type of solubiization with the solute dissolved in oriented clusters of the hydrotropic agent.

D. Stability

It consists chemical stability and physical stability to the existence of liquid solution.

 • Chemical stability

Techniques for prediction chemical stability of homogenous drug systems are well defined. Chemical instability of drug invariably is magnified in solution, opposed to solid or suspension systems. This liability, however, is to a large extent offset by the rapid and accurate stability predictions which are possible with homogeneous system but are extremely risk with heterogeneous dosage forms studies involving evaluation of stability in liquid drug system includes the effect of amino acids on the stability of aspirin in propylene glycol solution, and a systematic of the auto oxidation of polysorbates.

 • Physical stability

A physically stable oral liquid retain its viscosity, color clarity, taste and odor throughout its self-life. All of these characteristics can and should be evaluated subjectively and objectively if possible, during the course of stability assessment.

Suspensions

Suspensions are heterogeneous systems containing two phases. The continuous or external phase is generally liquid or semisolid and the dispersed or internal phase is made up of particulate matter that is essentially insoluble but dispersed throughout the continuous phase; the insoluble matter may be intended for physiologic absorption. Understanding of wetting, particle interaction, electro-kinetics aggregation and a sedimentation concept facilitates the making of good formulation for suspensions.

Capsule & Different types of Capsule

Capsules are solid preparations with hard and soft shells of various shapes and capacities, usually containing a single dose of active ingredient. They are intended for oral administration.

The solid shells of capsules are made of gelatin or other substances, the consistency of which may be adjusted by the addition of substances such a ‘glycerol or sorbitol. Excipients such as surface-active agents, opaque filters, antimi 1 preservatives, sweeteners, coloring matter and flavoring substances may be addeci, The content of capsules may be solid, liquid or of a paste-like consistency. They consist of one or more active ingredient with or without excipients such as solvents, diluents, lubricants and disintegrating agents. The contents do not cause deterioration of the shell. The shell, however, is attacked by the digestive fluids and the contents are released.

 Different types of Capsule

Several categories of capsules may be distinguished as

          • Hard capsules                               • Soft capsules

          • Gastro resistant capsules           • Modified release capsules

A. Hard capsules

Hard capsules have shells consisting of two prefabricated cylindrical sections, one end of which is rounded and closed, and the other being open.

B. Soft capsules

These have thicker shells than those of hard capsules. The shells consist of one part

And have various shapes.

C. Gastro resistant capsules

These are modified release capsules that are intended to resist the gastric fluid and to release their active ingredients in the intestinal fluid. They are prepared by providing hard or soft capsules with a gastro-resistant shell or by filling capsules with granules or with particles covered with a gastro resistant coating.

D. Modified-release capsules

Modified release capsules are hard or soft capsules in which the contents or the shell or both contain special excipients or are prepared by a special process designed to modify the rate or the place at which the active ingredient are released.

Tablet coating

The application of coating to tablets, which is an additional step in the manufacturing process, increases the cost of the product; therefore, the decision to coat a tablet is usually based on one or more of the following objectives

I. To mask of the unpleasant odor or color of the drug

2. To provide physical or chemical protection for the drug

3. To control the release of the drug from the tablet

 4. To protect the drug from the gastric environment of the stomach with an acid resistance enteric coating

5. To provide sequential drug release

6. To improve the pharmaceutical elegance the use of special color and contrasting printing

Tablet coating process

In most cases, the coating process is the last critical step in the tablet production cycle. The successful application of the coating solution formula to a tablet provides the visual characteristics for the product. This type of process chosen depends on the type of coating that is to be applied, durability of the core and the economics of the process. Because of the ever-increasing cost of energy and labor, the cost of the organic solvents and the associated environmental constrains, the economics of the process is receiving greater emphasis. There are three coating processes in pharmaceuticals, these areas-

• Film coating

• Enteric coating

• Sugar coating

 Criteria of film coating material

An ideal film coating material should have the following criteria

        I. Solubility in solvent of choice for coating preparation.

        2. Capacity to produce an elegant looking product.

        3. Stability in the presence of heat, light, moisture, air and the substrate being coated. The film properties should not change with aging.

        4. Essentially no taste, color or odor

Example of coating materials are-

        • Hydroxyl propylmethylcellulose US

       • Providon USP (1 -vinyl-2-pyrolidinone group)

Criteria of enteric coating material

An ideal enteric coating material should have the following criteria

a. Resistant to gastric fluid

b. Ready susceptibility or permeability to intestinal fluid

c. Compatibility with the drug substance

d. Stability in coating solution

e. Fonnation of a continuous film

f. Non toxicity and low costing.

Example: Sodiumsalicylate.

Manufacturing of Tablet

Tablets are prepared by compressing uniform volumes of particles or particle aggregates produced by granulation methods. In the manufacture of tablet cores means ensuring that they process a suitable mechanical strength to resist handling without crumbling or breaking. These may be demonstrated by examining the friability of uncoated tablets and the resistance to crushing. Chewable tablets are taken to ensure that they are crushed by chewing.

The manufacture of granule for tablet compression may follow one or a combination of three established methods -

(a) The dry methods of direct compression

(b) Compression granulation

(c) Wet granulation                                                                                                                                                                                     

(a) Direct compression

The vast majority of medicinal agents are rarely so easy to tablet, however in addition the compression of a single substance may produce tablets that do not disintegrate. If disintegration is a problem, the components are needed which in turn may interface with the compressibility of the active ingredient.

(b) Compression granulation (Slug process)

This is a valuable technique in situations where the effective dose of a drug is sensitive to heat moisture or both, which precludes wet granulation. Many aspirin and vitamin for mutations are prepared for tabletting by compressing granulation. Compression granulation involves the compaction of a tablet press or specially designed machinery, followed by milling and screening prior to find compression into a tablet. When the initial blend of powders is forced into the dyes of a large capacity tablet press and is compacted by means of flat faced punches, the compacted masses are called slugs, and the process is referred to as slugging. The slugs are then screened or milled to produce a granular form which now flows more uniformly than the original powder mixture.

 (c) Wet granulation

This technique uses as same as the two previously discussed granulation technique. The unique portion of wet granulation process involves the wet massing of the powder, wet sizing and drying.

Chemical Used for Manufacturing Tablet

Two types of chemical is used for manufacturing a table

     1. Active ingredients

     2. Excipients

1. Active ingredients: the active or necessary chemical for a specific medicine. As an example, for SILPOL (paracetamol) tablet the active ingredient is paracetamol.

2.  Excipients

Regardless of how tablets are manufactured, conventional oral tablets for ingestion usually contains the same classes of components in addition to the active ingredients, which are one or more agents functioning as:

                A • Diluents

                B • Binder or an adhesive

               C • Disintegrate

               D • Lubricant

In some tablet formulations may additionally require a flow promoter other more optional components include colorants and in chewable tablets, flavors and sweetness. All non-drug components of a formula are termed excipients. Some common tablet excipients are given below:

A. Diluents

 Microcrystalline cellulose, often referred to by the trade name Avicel, is a direct compression. Two tablets grades exist p1-1101 (powder) and pH 102 (granules).The flow properties of the materials are generally good and the direct compression characteristics are excellent. This is some what unique diluents in that while producing cohesive compacts, the materials also act as a disintegrating agent. It is however; relatively expensive used as diluents in high concentration and is thus typically combined with other material. As in the case of starch, microcrystalline cellulose is often added to tablet formulation for several possible functions. It is commonly employed exipients.

B. Binders and Adhesives

These materials are added either up or in liquid form during wet granulation to form granules or to promote cohesive compressed tablets.

C. Disintegrates

A disintegrate is added to most tablet formulation to facilitate a breakup or disintegration of the tablet when it contacts water in the gastrointestinal tract.

D. Lubricant, Antiadherent and Glidants

Lubricants are intended to reduced the friction during tablet ejection between the walls of the tablet and the die cavity in which the tablet was formed

Antiadherents have the purpose of reducing sticking or adhesion of any of the tablet granulation or powder to the faces of punches or to the die wall.

Glidants are intended to promote flow of tablet granulation or powder materials by reducing friction between the particles.

E. Colors, Flavors and Sweeteners

Colors are used for disguising of off-color drugs, product identification.

 Flavors are usually limited to chewable tablets and uses only for good flavors.

Sweeteners used for sweetening the tablet. Sugar coating is the example of sweeteners tablet.

Brief Description of Various Tablets

Uncoated Tablets

Uncoated tablets include single-layer tablets resulting from a single comparison of particles and multilayer tablets consisting of concentric or parallel layers obtained by successive comparison of particles of different composition.

Coated Tablets

Coated tablets are covered with one or more layers of mixtures various substances such as natural or synthetic resins, gums, gelatin, inactive and insoluble ifilers, sugars, plasticizers, polyols, waxes, coloring matters, flavoring substances. The substances used as coatings are usually applied as a solution or suspension in conditions in which evaporation of vehicles occurs. When the coating is veiy thin polymeric, the tablets are then known as film coated tablets.

Effervescent Tablets

Effervescent tablets are uncoated tablets generally containing acid substances and carbonates on hydrogen carbonates which reacts rapidly in the presence of water to release of C . They are intended to dissolve or to disperse in water before administration.

Soluble Tablet

Soluble tablets are uncoated or film coated tablets. They are intended to be dissolved in water before administration. The solution produced may be slightly opalescent due to added substances used in the manufacture of the tablets.

Dispersed Tablet

These tablets are uncoated or film coated tablets intended to be dispersed in water before administration giving a homogeneous dispersion.

Gastro resistant Tablet

These are modified release tablets that are intended to resist the gastric fluid and to release their active ingredients in the intestinal fluid. They are prepared by converting tablets with a gastro-resistant coating or from granule or particles already covered with a gastro-resistant coating.

Modified Release Tablet

These are coated or uncoated tablets containing special procedures which separately or together are designed to modify the rate or the place at which the active ingredient are released.

TABLET

Tablet contains one or more active ingredients and obtained by comprising uniform volumes of particles. Some are swallowed whole; some after being administered and some are retained in the mouth where the active ingredient is liberated. It may consists of excipients such as diluents, binders disintegrating agents, glidants , lubricants, coloring matters and agents etc.

Tablet end surfaces may be flat or convex. They may have lines or break marks and may bear a symbol or other markings. It may be coated or non-coated. Several categories of tables for oral use may be distinguished:

--Uncoated tablet

--Coated tablet

--Effervescent tablet

--Soluble tablet

--Dispersible tablet

--Gastro-resistant tablet

--Tablets for use in the mouth

--Modified release tablets

HPLC ASSAY METHOD FOR CEFUROXIME

Chromatographic System :

Column               : 25cm x 4.6mm, packed with particles of silica(5µm)

Flow rate             : 1.2ml / minute , so that the resolution factors between the peaks  corresponding to the Cefuroxime axetil diastereoisomers A & B  in solution(4)and between the peaks corresponding to Cefuroxime axetil diastereoisomer A & the Cefuroxime axetil A³ -isomer in  solution (2) are each not less than 1.5.

Wavelength                   : 278nm

Temperature       :Ambient

Injection volume : 20µL

Mobile Phase       : A mixture of 38 volumes of Methanol & 62 volumes of

                               0.2M Ammonium dihydrogen orthophosphate.

 Solution (1) :- Disperse 10 tablets in 0.2M Ammonium Dihydrogen Orthophosphate

previously adjusted to pH 2.4 with Orthophosphoric acid using 10ml per gm of the stated content of cefuroxime . Immediately add sufficient methanol to produce a solution containing the equivalent to 0.5%w/v of cefuroxime and shake vigorously.

Filter and dilute a quantity of the filtrate with sufficient mobile phase to produce a

solution containing the equivalent to 0.025% w/v of cefuroxime.

Solution (2) :- Heat a quantity of solution(1) at 60⁰ C for 1hour or until sufficient impurities (   ⁰   -isomers) have been generated.

 Solution (3) :- Expose  a quantity of solution(1) to ultraviolet light (254nm) for            24 hours or until sufficient impurities (E-isomers) have been generated.             Solution (4) contains 0.03% w/v of Cefuroxime Axetil CRS in mobile phase.

  All solutions containing Cefuroxime Axetil, if not to be used for immediate

  analysis, should be stored in the dark at a temperature 2º & 8º before analysis.

The retention times relative to Cefuroxime axetil diastereoisomer A are approximately 0.9 for Cefuroxime axetil diastereoisomer B , 1.2 for the Cefuroxime

axetil  A³-isomers and 1.7 & 2.1 for E-isomers .The relative standard deviation for the

response factor of Cefuroxime axetil for replicate injections of solution (1) is not more than 2.0%.

Calculate the content of C₂₀H₂₂N₄O₁₀S as the sum of the areas of the two peaks  corresponding to diastereoisomers A & B of Cefuroxime axetil using the declared

Content of C₂₀H₂₂N₄O₁₀S in Cefuroxime axetil CRS. Each mg of Cefuroxime axetil

Is equivalent to 0.8313mg Cefuroxime.

Assay of Montelukast Sodium (UV-VIS)Spectrophotometric Method

Assay of Montelukast Sodium (UV-VIS)Spectrophotometric Method.

Preparation of standard solution : Take 50mg of Montelukast Sodium in a 100ml volumetric flask, add 50ml of water and sonicate . Add 10ml of 1M Sodium

Hydroxide solution and dilute to 100ml with water. Transfer 1ml of this solution in a 50ml volumetric flask and dilute to 50ml with o.1N NaOH solution.

Preparation of sample solution :  Crush and finely powder 20 tablets. Weigh an amount of tablet powder containing 50mg of Montelukast Sodium in a 100ml volumetric flask, add 50ml of water and sonicate for about 10 minutes. Add 10ml of 1M NaOH soln. and dilute to 100ml with water, filter. Transfer 1ml of this solution in a 50ml volumetric flask and dilute to 50ml with 0.1N NaOH soln.

Measure the absorbance of the resulting solution at he maximum wavelength 345nm, using 0.1N NaOH as blank.

                                            Abs. of sample X Wt. of standard

% 0f Montelukast Sodium=---------------------------------------X potency of Standard

                                             Abs.of Std. X    Wt. of sample

HPLC ASSAY METHOD OF ASPIRIN

Preparation of Mobile phase :- Dissolve 2gms of sodium 1-heptasulphonate in a mixture of 850ml of water and 150ml of acetonitrile,and adjust with glacial acetic

acid to a pH of 3.4.

Diluting solution : Prepare a mixture of acetonitrile and formic acid (99:1)

Standard preparation : Dissolve an accurately weighed quantity of USP Aspirin RS in diluting solution to obtain a solution having a known concentration of about 0.5mg/ml

Assay preparation:  Weigh and finely powder not less than 20 tablets. Transfer an accurately weighed quantity of powder ,equivalent to about 100mg of aspirin ,to a suitable container. Add 20ml of diluting solution and about 10 beads. Shake vigorously for about 10 minutes, and centrifuse (Stock Solution).

Quantitatively dilute an accurately measured volume of the stock solution with

9 volumes of diluting solution (Assay preparation).

Chromatographic System :

Column                : 4.0mm X 30cm containing packing L1

Flow rate              : 2ml per minute.

Wavelength          : 280nm.     

Temperature                  : Ambient

Injection volume   : about 10µL.

Procedure : Seperately inject an equal volumes (about 10µL) of Standard preparation and Assay preparation into the chromatograph , record the chromatograms,and measure responses for the major peaks.

Calculate the quantity,in mg,of the aspirin (C₉H₈O₄) in the portion of the

tablets taken by the formula :

                                     200C(ru / rs),

In which C is the concentration, in mg per ml, of USP Aspirin RS in the standard preparation , an ru and rs are the peak responses of the aspirin peaks obtained from

the Assay preparation and the Standard preparation respectively.

ASSAY OF CLOPIDOGREL BISULPHATE BY HPLC METHOD

Preparation of phosphate buffer solution : Dissolve 2.72gms of monobasic potassium phosphate in about 500ml of water and dilute to 1000ml with same solvent. Adjust pH to 6.0 ± 0.1 with KOH.

Mobile Phase :  Prepare a filtered and degassed mixture of Phosphate Buffer and acetonitrile (35:65) .Make adjustment if necessary.

Standard Preparation : Dissolve 50mg 0f Clopidogrel Bisulphate Working Standard in methanol, sonicate and make volume to 50ml with methanol.Dilute 5ml of solution to 50ml with mobile phase (conc.0.1mg/ml). Filter the solution with 0.22µm before injection.

Assay Preparation : Crush finely 20 tablets into powder and weigh an amount of powder containg 100mg of Clopidogrel Bisulphate in a 100ml volumetric flask . Dissolve the content with methanol, sonicate and dilute with methanol to volume and mix, filter. Pipette 5ml of this solution to a 50ml volumetric flask, dilute with mobile phase to volume and mix.

Chromatographic System :

Column                  : 4.6mm x 25cm column that contains packing L1

Flow rate              : 1.5ml /min

Wavelength          : 265nm

Temperature                  : Ambient

Injection volume   : 20µL

The relative standard deviation (RSD) for replicate injections determined from Clopidogrel Bisulphate is not more than 1.0% .

Procedure :

Seperately inject equal volumes (about 10µL) of the standard preparation and the assay preparation into the chromatograph ,record the chromatograms, and measure the areas for all peaks . Calculate the quantity in mg of C₁₆H₁₆ClN0₂S.H₂S0₄ in

The portion of the tablet taken by the formula :

                                          Peak area of sample     Wt.of sample

% of Clopidogrel Bisulphate :------------------------X  --------------------X Potency of WS

                                           Peak of standard        Wt.of standard      

Where :  WS is the Working Standard .

Assay of Atorvastatin (UV-VIS) Spectrophotometric Method

Preparation of Standard Solution :  Take 10mg. of Atorvastatin Calcium Trihydrade in a 100ml volumetric flask, add 50ml of Methanol and sonicate , dilute to volume with the same solvent. Transfer 5ml of this solution in a 50ml Volumetric flask and dilute to volume with methanol.

Preparation of Sample Solution : Crush 20 tablets finely and weigh an amount of powder tablet containing 10mg of Atotvastatin Calcium Trihydrade in a 100ml Volumetric Flask ,add 50ml Methanol and sonicate , dilute to Volume with methanol and filter. Transfer 5ml of the filtrate in a 50ml volumetric flask and make volume with methanol.

Measure the absorbance of the resulting solutionat the maximum wavelength at 247nm,using a methanol as blank.

Calculation :

                        

                                Absorbance of sample x weight of standard

% of Atorvastatin = …………………………………………… X Potency of Standard                   

                                 Absorbance of Std.x Weght of sample x 1.084                                                                          

Sampling of Raw Materials

1.0      PURPOSE:  To ensure the smooth sampling of raw materials. It is important that the Sampling is done in an appropriate manner so that a representative sample is taken. 2.0      SCOPE:  Any materials related to manufacturing which is entering the warehouse, Must be sampled properly. 3.0      DEFINITIONS :  Nil 4.0      RESPONSIBILITY: QC officer 5.0      PROCEDURES: 5.1      After receipt of the material in the warehouse the store officer will send an Advice note to the QC department for sampling the material. The advice note Will contain in following information:             5.1.1        Name of the material 5.1.2        Name of the product 5.1.3        Country of origin 5.1.4        Control number of the product 5.1.5        Date of manufacturer 5.1.6        No. of containers received 5.1.7        Description of the containers received 5.1.8        Pack size of the containers.                    Sampling should be done in the following manner:                         5.2.1  Up to three containers        -       from one container                         5.2.2  From 4 to 5 containers       -       from 2 containers                         5.2.3  From 6 to 15 containers     -       from 3 containers                         5.2.4  From 16 to above               -       from every 5th container

Sample should be collected in inert container so that they do not react with the sample. For powdered materials samples should be taken with suitable sampling scoops made up of inert materials. For liquid this should be taken with glass sampling tubes. Suitable siphons may be used in case of sampling thick liquids. Amounts of sample taken should be at least twice the amount required for complete test.

Oral Liquid Manufacturing Flow Chart

 01.   Weighing &

    Mixing

       

02. Capsule

       Filling

03. Polishing

04.     Blistering

05. Inner Cartooning

06.    Master

Cartooning

. 

Disposal of Microbiological waste material

1.0        Purpose: To ensure a system adopted by Pharmaceuticals Limited for disposal of microbiological waste materials. 2.0        Scope: This SOP applies to the  waste materials generated in Pharmaceuticals Limited from microbiological work. 3.0        Definition: Nil. 4.0        Responsibility: Q.C Officer 5.0        Procedures: 5.1        Microbiological waste generated in the microbiological lab is heated under 15lb pressure at 1210C for half an hour in an autoclave machine. 5.2        After heating the autoclave machine is allowed to cool down. 5.3        Waste material is taken to a sink with water tap. Water tap is turned on & the waste material is allowed to drain off with sufficient water.

Calibration of UV- VIS Detector for HPLC

1.0      PURPOSE:  To ensure smooth functioning of HPLC Machine. 2.0      SCOPE  :  The SOP applies to the calibration of UV-VIS detector of Shimadzu                          Company model No. SPD-10A vp. 3.0   DEFINITION:    Nil. 4.0 RESPONSBILITY:  Quality Control officer. 5.0  PROCEDURES: 5.1      Press & hold down the “shift” key & turn the power switch on. 5.2      Press the “func” key until lamp is displayed. 5.3      Press  “1”, then enter. 5.4      Press “func” until “Wave check” is displayed. 5.5      Press “enter”. The wavelength accuracy check is run automatically. CHECK GOOD should appear on the screen when the test ends.

Calibration of Spectrophotometer

1.0   PURPOSE:   To ensure smooth functioning of Spectrophotometer. 2.0   SCOPE   :   The SOP applies to the calibration of Spectrophotometer of Shimadzu                             Company model No. UV-1201 3.0   DEFINITION:  Nil. 4.0  RESPONSIBILITY :  QC officer. 5.0  PROCEDURE: 5.1  Switch on the machine & wait for auto calibration . 5.2  After auto calibration check the absorbance of potassium Dichromate Solution VS at the wavelengths indicated in the following table which gives for each Wavelength the exact value of A (1% 1cm) & the permitted limits. The tolerance of absorbance is ± 0.01           Wavelength (nm)                     A(1% 1cm)                     Maximum Tolerance                     235                        -                124.5           -                  122.9 – 126.2                  257                        -                 144.0           -                  142.4 – 145.2                  315                        -                 48.6            -                    47.0 – 50.3                  350                        -                 106.6           -                   104.9 – 108.2