5.0 materials and instruments 5.1 materials 5.1.1 drugs...

Materials and Instruments Chapter 5

Formulation and Evaluation of Nanoparticles For Better Drug Bioavailability 5-1

5.0 MATERIALS AND INSTRUMENTS 5.1 Materials 5.1.1 Drugs and excipients

a) Chitosan (Marine chemicals, Cochin, India)

b) Poly lactic co- glycolic acid (Purac Biochem, Netherland)

c) Simvastatin and Lovastatin (Aurobindo Pharmaceuticals, Hyderabad)

d) Sodium tripolyphosphate (Loba chemie, Mumbai)

e) Cholesterol (Himedia Laboratories Pvt. Ltd., Mumbai)

f) Mannitol (S. D. Fine Chem Ltd., Mumbai)

g) Carboxy methyl cellulose (Colorcon Asia Pvt Ltd. Goa)

h) Hydroxy propyl methyl cellulose (Colorcon Asia Pvt Ltd., Goa)

i) Pluronic F 68 (BASF, Germany)

5.1.2 Chemicals and reagents

a) Potassium dihydrogen phosphate (Loba chemie, Mumbai)

b) Disodium hydrogen phosphate (Loba chemie, Mumbai)

c) Ethanol (Loba chemie, Mumbai)

d) Methanol (Finar chemicals Ltd., Ahmedabad)

e) Acetonitril HPLC grade (Finar chemicals Ltd., Ahmedabad)

f) Sodium hydroxide (Finar chemicals Ltd., Ahmedabad)

g) Acetic acid (Finar chemicals Ltd., Ahmedabad)

h) Acetone (Finar chemicals Ltd., Ahmedabad)

i) Dialysis bag (Hi-Media, Mumbai)

j) Lipidemic reagents kit (Merck, India Ltd., Mumbai)

k) Microcentrifuge tubes and microtips (Tarson Pvt. Ltd. Kolkatta, India)

l) Micropipette (Bioera medical system, Pune)

m) Membrane filter (Millipore, Bedford, USA)

5.1.3 Instruments and equipments

a) UV-Visible spectrophotometer (Jasco V-630, Shimadzu, Japan)

b) Rotatotry Evaporator (Evator, Medica Instruments, MFG Co)

c) Dissolution test apparatus (USP Type II, Electrolab (TDT 08 L,

12, Mumbai)

d) FT Infrared Spectrophotometer (Shimadzu Jasco 4100, Japan)

e) Ultrasonicator (Spectra Lab., Mumbai)

f) Digital balance (Shimadzu AY-220, Japan)

g) Stability Chamber (Aditi enterprises, Mumbai)

h) Hot air oven (Sai Enterprises Works, Mumbai)



i) Orbital Shaker (Remi Motors Ltd., Mumbai)

j) Differential scanning calorimeter (TA-60, Instruments SDT-2960,

USA)

k) Powder X-Ray Diffractometer (Bruker axs D8 (Bruker, Karlsruhe,

medisone,USA)

l) Scanning Electron Microscope (JEOL, JSM 6360, equipped with auto

fine coater, Tokyo, Japan)

m) Cooling centrifuge ( 20, 000 rpm) (Remi Motors Ltd., Mumbai)

n) Melting point apparatus (Veego instruments, Mumbai)

o) Freeze Dryer (Martin Christ, ALPHA 1-2 LD PLUS)

p) Particle Size analyzer (Mastersizer 2000 ver 2.00 Malvern instrument,

Nano-ZS, malvern UK)

q) Transmission Electron Microscope (Tecnai G2,20 U-Twin, FEI,

Netherland)

r) High Performance Liquid Chromatography (Jasco HPLC PU-2080 &

UV- 2075)

s) Micro centrifuge (Remi Motors Ltd., Mumbai)

t) Rotatory tablet machine (Rimek minipress, Mumbai )

u) Homogenizer ( Ika India Pvt. Ltd. Banglore )

v) Magnetic Stirrer (Remi Motors Ltd., Mumbai)

5.1.4 Softwares used

a) PCP disso. V3, Pune for dissolution data processing.

b) Spekwin 32 bit, Friedrich meneche, for data acquisition and processing

of FTIR.

c) Malvern software ver. 5.2 for particle size data acquisition and

processing.

d) STARe version 5.5, mettler Toledo for processing thermogram obtained

by DSC

e) Graphpad prism Ver. 5.04 for stastical data processing.

f) OIRIGIN Pro ver. 8.0 orgilab corp. USA for PXRD data analysis.

5.1.5 Animals used

a) Albino rats wister strain of either sex procured from Appasaheb

Birnale, College of Pharmacy, Sangli

b) Albino rabbits of either sex procured from Govt. College of Pharmacy,

Karad.



5.2. SIMVASTATIN 109

Synonym : Velastatin, Synvinolin

Structural Formula :

Structure of Simvastatin

Molecular Formula : C25H38O5

Molecular Weight : 418.6 Dal

Chemical Name : 1 S-[1,3,7,8 (2S*,4S*),8_] ]-1,2,3,7,8,8 a hexahydro-3,

7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-

pyran-2yl)ethyl]-1-naphtalenyl-2,2-imethylbutanoate

Category : HMG CoA reductase inhibitor, Anticholesteremic Agent

Description : White to off-white, nonhygroscopic, crystalline powder

Melting Point : 135- 138oC

Partition Coefficient : Log P (Octanol / Water) 4.68

Solubility Insoluble in water (0.03g/L), n-hexane (0.15g/L) and hydrochloric acid (0.1M) (0.06g/L); Soluble in chloroform (610g/L), DMSO (540g/L), methanol (200g/L), ethanol (160g/L), polyethylene glycol (70g/L), sodium hydroxide (0.1 M) (70g/L) and propylene glycol (30 g/L). Storage: To be stored below 25°C, protected from light and moisture. Dose: An initial dose of 10 mg daily is administered with a maximum of 80 mg daily. Mechanism of action



Simvastatin is a methylated derivative of lovastatin that acts by competitively inhibiting 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. Absorption Absorption of simvastatin, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. Pharmacokinetic Simvastatin is a prodrug metabolised in the liver to form the active β-hydroxyacid derivative. This inhibits the conversion of HMG-CoA to mevalonic acid by blocking HMG-CoA reductase, an early and rate-limiting step in cholesterol biosynthesis. It reduces total cholesterol, LDL-cholesterol and triglycerides and increases HDL-cholesterol levels. Pharmacokinetic parameters of simvastatin shown in Table 5.1. Disposition in the Body Simvastatin is a pharmacologically inactive pro-drug which is rapidly metabolized mainly to simvastatin β hydroxy acid analogue (with maximum concentration being reached within 1.3 -2.4 h. after dosing) which is inhibitor of HMG-CoAreductase. Other metabolites includes 3-hydroxy, 3-hydroxy-3–methyl analogue and 3-oxomethylene derivatives and analogues of 6- hydroxymethyl- and 6-carboxylic acid of which chiral centre at position 6 has been inverted ( these are biliary metabolites). The drug and its metabolites are excreted in urine (13%) and faeces (60%) which include both the unabsorbed drug and drug excreted in bile.

Table 5.1: Pharmacodynamics / Pharmacokinetics parameters of simvastatin

Parameters Values

Onset of action LDL-cholesterol reductions: 3 days

Peak effect 2 weeks

Absorption Absorbed from the GI tract (oral), 85%

Metabolism Extensively hepatic

Excretion In the faeces as metabolites (60%); Urine (10- 15% inactive form)

Bioavailability β hydroxy acid, 5%

Half life Simvastatin 2 hrs; β hydroxy acid 1.9 hrs

Protein binding Simvastatin 98% and β hydroxy acid 94 %.

T max 1.3 – 2.4 h

LD 50 3 g/kg (Mice); 4438 mg/kg (Rats); >5 g/kg (dog)



Adverse effects Headache, myalgia, flatulence, constipation, abdominal pain, nausea, dyspepsia, diarrhea. Contraindications Acute liver disease or unexplained persistent elevations of serum transaminases. Pregnancy, lactation, Porphyria. Brand Names Cholestat, Coledis, Colemin, Corolin, Labistatin, Lipex, Zocor, Simovil, Sinvacor, Sivastin, Vasotenal.

LOVASTATIN 109

Synonym : Mevinolin, Monacolin K and Mevacor®, L-154803; MB-530B; MK-803; MSD-803; Monacolin K; 6α- Methylcompactin; Mevinolin Proprietary names : Lipofren; Lovalip; Mevacor; Mevinacor; Mevlor; Nergadan; Sivlor; Taucor Structural Formula :

Structure of Lovastatin CAS number : 75330–75–5

Molecular Formula : C24H35O5

Molecular Weight : 404.5 Dal

Chemical Name : [1S-[1α(R),3α,7β,8β(2S,4S), 8aβ]]-1,2,3,7, 8,8a- hexahydro-3,7- dimethyl-8-[2-(tetrahydro-4-hydroxy-6- oxo- 2H-pyran-2-yl)ethyl]- 1naphthalenyl 2- methylbutanoate Category : 3-hydroxy-3-methylglutarylcoenzyme reductase inhibitor Description : White, nonhygroscopic, crystalline solid powder Melting Point : 174.5- 176 oC Partition Coefficient : Log P (Octanol / Water) 4.26 Purity : ≥ 98 %



Limit for assay Each tablet contains not less than 90% and not more than 110% of the labeled amount of lovastatin. Description Lovastatin is a cholesterol-lowering agent that belongs to the class of medications called statins. It was discovered by Alfred Alberts and his team at Merck in 1978, after screening only 18 compounds over 2 weeks. The agent, also known as mevinolin, was isolated from the fungi Aspergillus terreus. Solubility It is practically insoluble in water (0.4×10−3g/L) and petroleum spirit; sparingly soluble in low molecular weight alcohols (methanol, 28 g/L, ethanol, 16 g/L, isopropanol 20 g/L); soluble in acetone and acetonitrile; freely soluble in chloroform. Storage: To be stored below 25°C, protected from light and moisture. Symptoms of overdose: Nausea, diarrhea, stomach distress, indigestion. Mechanism of action Lovastatin acts by competitively inhibiting 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. The mode of action of statins is HMG-CoA reductase enzyme inhibition. This enzyme is needed by the body to make cholesterol. Pharmacokinetic parameters of lovastatin shown in Table 5.2.

Table 5.2: Pharmacodynamics / Pharmacokinetics parameters of lovastatin

Parameters Values

Onset of action LDL-cholesterol reductions: 3 days

Absorption 30%; rapidly absorbed following oral administration

Distribution Distributed mainly to the liver; crosses the blood- brain barrier, crosses the placenta.

Excretion Hepatic; extensive first-pass effect

Bioavailability < 5 %

Half life Simvastatin 2 hrs; β hydroxy acid 1.9 hrs

Protein binding Lovastatin and β hydroxy acid metabolite (> 95%)

T max 1.1-1.7 h

Creatinin clearance 10-30 ml/min.

LD50 1000 mg/kg (orally in mice)



Pharmacodynamics Lovastatin lowers hepatic cholesterol synthesis by competitively inhibiting HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the cholesterol biosynthesis pathway via the mevalonic acid pathway. Decreased hepatic cholesterol levels causes increased uptake of low density lipoprotein (LDL)-cholesterol, and reduces cholesterol levels in the circulation. At therapeutic doses, lovastatin decreases serum LDL cholesterol by 29-32%, increases high density lipoprotein (HDL) cholesterol by 4.6-7.3%, and decreases triglyceride levels by 2-12%. HDL cholesterol is thought to confer protective effects against CV disease, whereas high LDL and triglyceride levels are associated with higher risk of disease. Adverse effects Muscle cramps, myalgia, myopathy, dysfunction of certain cranial nerves, dizziness, vertigo, memory loss, polymyalgia rheumatica, dermatomyositis, pancreatitis, hepatitis, alopecia, pruritus, loss of libido, erectile dysfunction. Contraindications Hypersensitivity to lovastatin or any component of the formulation active liver disease unexplained persistent elevations of serum transaminases; pregnancy; breast feeding. Route of elimination Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. 83% of the orally administered dose is excreted in bile and 10% is excreted in urine. POLYLACTIC CO-GLYCOLIC ACID Chemical name : 3,6-dimethyl-1,4-dioxane-2,5-dione;1,4-dioxane-2,5- dione, polymer and copolymer thereof. Chemical family : Polyester Common names : PGA; Poly(D,L-lactide-co-glycolide) Chemical formula : (C6 H8 O4 )x, (C4 H4 O 4 )y, (C6 H8 O4 )x(C4 H4 O4 )y. CAS number : 26780-50-7 Structural formula :

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Structure of Poly(D,L-lactide-co-glycolide)

Solubility Chlorinated solvents, tetrahydrofuran, acetone or ethyl acetate, methylene chloride, chloroform, dimethyl formamide. Physicochemical properties of PLGA Commercially available PLGA polymers are usually characterized in terms of intrinsic viscosity, which is directly related to their Molecular weight. The mechanical strength, swelling behavior, capacity to undergo hydrolysis and subsequently the biodegradation rate is directly influenced by the crystallinity of the PLGA polymer. The resultant crystallinity of the PLGA co-polymer is dependent on the type and the molar ratio of the individual monomer components (lactide and glycolide) in the copolymer chain. PLGA polymers containing a 50:50 ratio of lactic and glycolic acids are hydrolyzed much faster than those containing a higher proportion of either of the two monomers. PLGA is highly crystalline because it lacks the methyl side groups of the PLA. Lactic acid is more hydrophobic than glycolic acid and, therefore, lactide-rich PLGA co-polymers are less hydrophilic, absorb less water and, subsequently, degrade more slowly. The Tg of the PLGA co-polymers are above the physiological temperature of 37°C and hence they are normally glassy in nature. Thus, they have a fairly rigid chain structure, which gives them significant mechanical strength to be formulated as a degradable device. The physical properties of PLGA shown in Table 5.3.

Table 5.3: Physical Properties of PLGA

Parameters Values

Appearance White to off-white fluffy to fibrous substance

Odour Nearly odourless

Polymer composition 50:50 molar ratio D,L-lactide : glycolide

Molecular weight 350,000-500,000 Dal

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Inherent viscosity 1.60-1.99 dl/g

Glass transition Temperature 40- 60ºC

Specific gravity 1.33 g/ml

Residual monomer max. 0.5 % D,L-lactide monomer & max. 0.5 % glycolide monomer

Residual solvent max. 0.1 % acetone, max. 890 ppm toluene

Water max. 0.5 %

Sulphated ash max. 0.1 %

Degradation time Appox. 23 months

Biodegradation In both in vitro and in vivo, the PLGA co-polymer undergoes degradation in an aqueous environment (hydrolytic degradation or biodegradation) through cleavage of its backbone ester linkages. The polymer chains undergo bulk degradation and the degradation generally occurs at a uniform rate throughout the PLGA matrix. The carboxylic end groups present in the PLGA chains increase in number during the biodegradation process as the individual polymer chains are cleaved. These are known to catalyze the biodegradation process. It has also been reported that large fragments are degraded faster internally and amorphous regions degrade faster than crystalline regions. The biodegradation rates of the PLGA co-polymers are dependent on the molar ratio of the lactic and glycolic acids in the polymer chain, M.W. of the polymer, the degree of crystallinity and the Tg of the polymer. Application Preparation of PLGA and its co-polymer-based nanoparticles, emulsification solvent evaporation/diffusion method, salting-out method, nanoprecipitation method, Polymeric nanomicelles, Nano/Microparticles, hydrogels, injectable drug delivery systems, controlled-delivery applications, produce a variety of biodegradable sutures, staples, fixation rods, screws and clips, bone repair applications, and have been found to be biocompatible, non-toxic and non-inflammatory. Polylactide/polyglycolide polymers in the field of orthopaedics have seen enormous growth, especially as fracture fixation devices and scaffolds for tissue growth. The biodegradable and biocompatible nature of these polymers as well as their suitable mechanical properties have made them potential candidates for a variety of orthopaedic applications; such as bone fixation repair of osteochondral defects, ligament and tendon reconstructions, and bone substitutes. PLGA is a suitable biomaterial or polymer for the preparation of novel drug delivery systems due to its biodegradability and biocompatibility.110



CHITOSAN

Nonproprietary names : USP: Chitosan Chemical name : 2-Amino-2-deoxy-(1,4)-β-D-glucopyranan; deacetylated chitin; deacetylchitin; β-1,4-poly-D-glucosamine; poly- D-glucosamine; poly-(1,4-β-D-glucopyranosamine)

Structural formula :

Structure of Chitosan

CAS registry No : 9012-76-4 Functional Category : Coating agent, disintegrant, film forming agent, mucoadhesive, tablet binder, viscosity- increasing agent Description Partial deacetylation of chitin results in the production of chitosan, which is a polysaccharide comprising copolymers of glucosamine and N-acetylglucosamine. Chitosan is the term applied to deacetylated chitins in various stages of deacetylation and depolymerization and it is therefore not easily defined in terms of its exact chemical composition. Chitosan is a cationic polyamine with a high charge density at pH <6.5, and so adheres to negatively charged surfaces and chelates metal ions. It is a linear polyelectrolyte with reactive hydroxyl and amino groups (available for chemical reaction and salt formation). Specification of pharmaceutical grade chitosan shown in Table 5.4. The properties of chitosan relate to its polyelectrolyte and polymeric carbohydrate character. The presence of a number of amino groups allows chitosan to react chemically with anionic systems, which results in alteration of physicochemical characteristics of such combinations. The nitrogen in chitosan is mostly in the form of primary aliphatic amino groups. Chitosan therefore undergoes reactions typical of amines: for example, N-acylation and Schiff reactions. Almost all functional properties of chitosan depend on the chain length, charge density, and charge distribution. Numerous studies have demonstrated that the salt form, molecular weight, and degree of deacetylation as well as pH at which the chitosan is used all influence how this polymer is utilized in pharmaceutical applications.111

Solubility Sparingly soluble in water; practically insoluble in dichloromethane (95%), other



organic solvents and neutral or alkali solutions at pH above approximately 6.5. Chitosan dissolves readily in dilute pharmaceutical excipients and concentrated solutions of most organic acids and to some extent in mineral inorganic acids (except phosphoric and sulfuric acids). Upon dissolution, amine groups of the polymer become protonated, resulting in a positively charged polysaccharide (RNH+3) and chitosan salts (chloride, glutamate etc.) that are soluble in water; the solubility is affected by the degree of deacetylation.

Table 5.4: Specification of Pharmaceutical-Grade Chitosan

Parameters Description

Appearance (powder or flake) White or yellow

Particle size < 30 µm

Viscosity ≤ 5 cps

Density between 1.35 to 1.40 g/ml

Molecular weight 50,000 to 2,00,000 Dal

Glass transition temp 140 -150°C

pH 6.5 to 7.5

Moisture content > 10 %

Ash value > 2 %

Mater insoluble in water ≤ 0.5 %

Degree of deacetylation 66 % to 99.8 %

Heavy metal (Pb) < 10 ppm

Heavy metal (As) < 10 ppm

Protein content < 0.3 %

Loss on drying ≤ 10 %

Applications Chitosan is used in cosmetics and is under investigation for use in a number of pharmaceutical formulations. The suitability and performance of chitosan as a component of pharmaceutical formulations for drug delivery applications has been investigated in numerous studies. These include controlled drug delivery applications, use as a component of mucoadhesive dosage forms, rapid release dosage forms, improved peptide delivery, colonic drug delivery systems and use for gene delivery. Chitosan has been processed into several pharmaceutical forms including gels, films, beads, microspheres, tablets, and coatings for liposomes. Furthermore, chitosan may be processed into drug delivery systems using several techniques including spray-drying, coacervation, direct compression and conventional granulation processes.



Storage Chitosan is stable material at room temperature. Chitosan should not be stored in tightly closed container in a cool and dry place. PLURONIC F- 68

Non-Propriety name : Poloxamers BP, Poloxamera Ph Eur, and Poloxamers USP/NF Synonyms : Lutrol, Monolan, pluronic, supronic, Synpernonic, Poloxalkol, polyethylene- propylene glycol copolymers, polyoxyethylene- polypropylene copolymer. CAS registry no. : 9003-11-6 Chemical name : alpha-Hydroxy- 3- hydroxypoly (oxyethylene) poly(oxypropylene) polyoxyethylene bock copolymer. Molecular formula : (C2H40)a(C3H6)b(C2H40)a H where a=12 and b=20 Structural formula :

Structure of Pluronic F-68

Molecular weight : Molecular weight ranging from 7680 to 9510 Da pH : 5.0-7.5 Specific gravity : 1.06 g/ml Viscosity : 1000 cps Melting point : 52 -57ºC Cloud point : 100ºC Description Poloxamers are non-ionic poly (ethylene oxide) (PEO) – poly (propylene oxide) (PPO) copolymers. They are used in pharmaceutical formulations as surfactants, emulsifying agents, solubilizing agent, dispersing agents and in vivo absorption enhancer. Poloxamers are often considered as “functional excipients” because they are essential components and play an important role in formulation. Their surfactant property has been useful in detergency, dispersion, stabilization, foaming, and emulsification.112

Solubility



Pluronic F68 is freely soluble in ethanol, water and sparingly soluble in propranolol. Category Dispersing agent, emulsifying agent, co-emulsifying agent, solubilising agent, tablet lubricant, wetting agent. Application Poloxamer hydrogel is used for the assessment of biofilm susceptibility towards biocide treatments. Surfactant Pluronic F68 decreases inflammation and tissue damage after experimental brain injury in rats. The surfactant, Pluronic F68 has been found to protect against tissue injury in various experimental models. Its protective mechanism may involve the effects of the surfactant against oxidative stress and inflammation. Temporary vascular occlusion with poloxamer 407, Poloxamer 407 is used as an intraperitoneal barrier material for the prevention of postsurgical adhesion formation and reformation in rodent models for reproductive surgery. Improvement in capillary blood flow in the zone of stasis after burn injury, lens refilling with poloxamer hydrogel, Prevention of adult skeletal muscle cells necrosis. The new findings have demonstrated immuno-modulation and cytotoxicity-promoting properties of Poloxamers revealing significant pharmacological interest and hence, human trials are in progress to specify these potential applications. Grades available The common available grades are poloxamer F88, poloxamer F 98, poloxamer F188, 237, poloxamer 338, and poloxamer 407, Pleuronic10R5, Pleuronic17R2, Pleuronic 25R2, Pleuronic 31R1, Pleuronic F 108, Pleuronic F 127 NF, and Pleuronic F38. SODIUM TRIPOLYPHOSPHATE (STPP) Synonyms : Pentasodium triphosphate Chemical name : Sodium Tripolyphosphate Anhydrous Chemical formula : Na5P3O10 CAS registry No. : 7758-29-4 Structural formula :

Structure of Sodium Tripolyphosphate



Appearance : White to off-white powder Odour : Nearly odourless Bulk Density : 0.5-1.2 g/ml Melting point : 622- 647 ºC Solubility : 14.5 g anhydrous salt in 100 ml water at 25 ºC pH Value : 9.8 at 20 ºC (1% soln.) Molecular weight : 367.86 Dal Purity : 94.0% Preparation and properties Sodium tripolyphosphate is produced by heating a stoichiometric mixture of disodium phosphate, Na2HPO4, and monosodium phosphate, NaH2PO4, under carefully controlled conditions. Na2HPO4 + NaH2PO4 → Na5P3O10 + 2 H2O Specifications Main content (Na5P3O10) % ≥95.0, P2O5%≥57.0, Water Insoluble%≤0.05, SO4 %≤ 0.4, Heavy metal (Pb) % ≤0.001, Arsenic(As) % ≤0.0003, Fluoride(F) % ≤0.003, Chloride (Cl) % ≤0.025 and Whiteness % ≥85.0. Application Used as one of the main auxiliaries for synthetic detergent, synergist for soap; water softener, tanning agent for leather making, auxiliary for dyeing. As an effective as dispersion agent for suspension, solutions of coatings, kaolin, magnesium oxide, calcium carbonate and drilling mud etc., as an oil contamination resistance agent in paper production. In foodstuff industry it is used as quality improver in the process of canned food, fruit juice drinks, foodstuffs from milk or soybeans. It may tender the meat in canned ham and soften the skin of horse bean in canned horse bean. It may also serves as a softener or densifier in foodstuff industry. STPP is a preservative for seafood, meats, poultry, and animal feeds.113

Polyphosphates are hydrolyzed into simpler phosphates, which in moderate amounts are nutritious. For example, ATP, a related derivative of triphosphate, is essential for life. Thus, the toxicity of polyphosphates is low, as the lowest LD50 after oral administration is >1,000 mg/kg body weight. Similarly, no mutagenic or carcinogenic effects nor reproductive effects have been noted. Salts of polyphosphate anions are moderately irritating to skin and mucous membrane because they are mildly alkaline.

Storage: Store in original, unopened package in clean, cool, dry place.

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