Fermentation. Unit Processes Review - Industrial & Engineering

an

(I/ECIUnit Processes Review

Fermentation by Arthur E. Humphrey, University of Pennsylvania, Philadelphia, Pa. Fred H. Deindoerfer, Industrial Biochemicals, Inc., Edison, N. J . increasing attention to control of process variables marks continued growth of fermentation as an industrial processing method T H E YEAR 1960 witnessed increasing progress in the application of fermentation as a processing method in the chemical industry. New technical advances in the biosynthesis of amino acids and antibiotics and in the transformation of steroids were most noticeable. Interest continues strong in such areas as continuous fermentation and process control, as well as in the problem of oxygen transfer. The importance of continuous fermentation was reflected in the second International Symposium on Continuous Cultivation in London. Fermentation cngineering, ncw process applications of microorganisms, and microbial genetics were the main topics of discussion a t the first International Fermentation Symposium held in Rome. Of particular note during the past year has been the tremendous contribution of foreign scientists to progress in fermentation. This is the condensed version of a complete fermentation process reviebv which covers the pertinent literature and patents published during 1960. T h e uncondensed review, containing 742 references, is available from the School of Chemical Engineering, Gniversity of Pennsylvania, Philadelphia 4, Pa.

Ethanol. A review oiethanol production in Brazil from can? sugar molasses was prepared by Drews ( 2 A ) . T h e presently employed semicontinuous method of ethanol fermentation, with as many as 10 stages in the fermentation system. was described by Yarovenko (20.4). Some of the operating problems oi this multistage system were discussed. Other publications dealing with the ethanol fermentation are summarized in Table I. Glycerol. A continuous process for glycerol production from sugar by the bisulfite fermentation process was reported by Harris and Hajny (7A). Sugar-KaHSOS solutions were converted by yeast to glycerol in 25.670 yield based on sugar charged. Recovery procedures were also described.

Organic Acids Acetic Acid. A Formosan plant producing 2 tons per day of acetic acid in greater than 90% theoretical fermentation yield from ethanol was described ( 9 B ) . Allgeier and Hildebrandt (3B) summarized recent developments in vinegar manufacture and compared various equipment for this fermentation.

Modern techniques now employed are similar to submerged fermentation as used in antibiotic manufacture. Citric Acid. In a search for new strains capable of producing citric acid, Terada and others (29B) found that Trichoderma uiride produced citric acid from glucose or starch in yields as high as 8.5%. A patent was issued to Kinoshita (15B) for this fermentation. .4nother patent was granted (18B) for ihe production of citric acid using either Penicillium adametzi or P . restrictum. Extensive studies \yere made by I m senecki and others (17B, IZB) and Verbina (30B) of the morphological characteristics, citric-acid-producing capabilities, and respiratory activity of Aspergillus niger mutants produced by ultraviolet irradiation of a Russian industrial strain. Table I1 summarizes other studies on citric acid fermentation by il. niger strains using stationary and submerged culture techniques. Fumaric Acid. Using a strain of Rhizopus arrhizus, Rhodes and others (26B) obtained fumaric acid yields of 6.5% from glucose. Three-day fermentations of 10 to 13yc glucose media were achieved. Based on these studies, a practical process for fLimaric acid pro-

Solvents Acetone and Butanol. A new strain, Clostrzdium saccharuperbut~lacetunicum, for producing butanol and acetone was patented by Hongo ( 8 A ) . Another new species, C. aurantiacum. was found to produce butanol by Sutoh and others (19A) Calleo and Montoya ( I A ) investigated the role of acetaldehyde and suggested that it is a precursor in the formation of ethanol in the butanol-acetone fermentation. Pomar and Emiliani (17A) demonstrated that acetic and butyric acid accumulation causes cell lysis. When these acids were neutralized during fermentation, a threefold increase in cell population resulted. Other studies of the acetone-butanol fermentation are summarized in Table I.

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INDUSTRIAL AND ENGINEERING CHEMISTRY

The authors were fortunate in receiving the support of the foreign collaborators listed below in reviewing the 1960 literature:

Shuichi Aiba, University of Tokyo, Tokyo, Japan Jeronimo Angulo, Institute of Chemistry, Madrid, Spain K. Beran, Biological Institute, Prague, Czechoslovakia F. Dentice di Accadia, Istituto Superiore di Santa, Rome, Italy T. K. Ghose, Jadavpur University, Calcutta, India Hans Klaushofer, Versuchsstation f.d. Garungsgewerke, Vienna X V I I I , Austria Ivan Malek, Biological Institute, Prague, Czechoslovakia h e Moller, Svenska Sockerfabriks Aktiebolaget, Arlov, Sweden J. Philippe and F. Zuckerkandl, Socigt6 Industrielle pour la Fabrication des Antibiotiques, Seine, France

Table I.

Fermentation Production of Solvents

Investigation

Results Acetone and Bytanol Methods of increasing ratio of butanol to other solvents Solvent production started earlier, Addition of calcium acetate to glucosecontaining mash proceeded faster 40-60% of carbohydrate requirement Use of cornstalk hydrolyzate in wheat supplied by cornstalks mash and corn gluten mash Up to 50% mash make-up water conStillage recycle served Each fermentor corresponded to ferContinuous multistage fermentation in mentation stage. Unsterile feed 11 fermentors produced contamination or instability in 6 to 11 days. Aseptic techniques permitted 28-day fermentation without contamination Ethanol

Economic comparison of ethanol production in Poland (from potatoes, molasses, sulfite liquors) with synthetic ethanol Molasses supplementation of starch grain mashes in Russian distilleries Mash prepared from tapioca tuber Stirring mash mechanically and by CO1 sparging Deionization of cane molasses for ethanol production Ester and aldehyde distillery fraction recycled to mash prior to and during fermentation NH4F addition to cane molasses mash Fermentation system employing parallel stages

Fermentation ethanol cheaper than synthetic High quality stillage for cattle feed 35-gal. 200-proof ethanol per ton tuber Fermentation period reduced; grain containing husks fermented without pretreatment Higher fermentation efficiency, slower fermentation rate Decrease in side-product formation, increase in alcohol yield Preservative, protective, accelerational effect Economic advantages in equipment requirements

duction utilizing fermentation appears a distinct possibility. Gluconic Acid. Optimal conditions for the production of gluconic acid by a species of Candida isolated from fruit were described by Takano (28B). Yields of 87% were obtained in a 10% glucose medium. Itaconic Acid. Extensive studies of the itaconic acid fermentation employing A . terreus were carried out by Buendia and Garrido (6B, 7B). They found a medium containing 10% invert sugar supplemented with a small amount of cane molasses, as well as a nitrogen source, yielded 60% conversion in about three days. Re-use of the mycelia increased the conversion as high as 77% and shortened the fermentation cycle considerably. Kobayashi (76B, 77B) received patents for a process producing itaconic acid from saccharified wood chips using A . itaconicus and for a semicontinuous process in which nutrients and mycelia are intermittently added to a fermentation which is controlled in a favorable p H range. Lactic Acid. The prospects for lactic acid achieving a more prominent position as a chemical intermediate were reviewed by Arnold and Childs (4B). Various nitrogen sources were evaluated by Balatti and Ertola (5B) in the fermentation of 3Oy0 molasses solutions using Lactobacillus delbrueckii. Use of malt sprouts, corn steep liquor, an3

Penicillium mycelia resulted in good yields. Ziobrowski and Zmaczynski (378) found that replacement of malt sprouts by wheat germ shortened the fermentation of 13% sucrose solutions by L. delbrueckii about 25%. Lactic acid production by the same organism in treated molasses solutions was studied by Buntova and others (8B); they obtained high yields in two to three days’ fermentation time. The formation of lactic acid by Clostridium acetobutylicum was studied by Katagiri and others ( 1 4 3 ) ; 9770 of the glucose consumed was converted to lactic acid. O t h e r Organic Acids. A coli-aerogenes bacterium produced yields of a-ketoglutaric acid as high as 55% from glucose. Katagiri and Tochikura (73B) demonstrated that pyruvic acid was a precursor in this fermentation. Abe and others (7B) discussed the formation of pyruvic acid by bacteria. These same workers ( 2 8 ) also investigated the cultural conditions for malic acid production by several strains of Aspergzlli. Recent studies of other organic acids produced by fermentation are summarized in the uncondensed review.

Amino Acids Interest in amino acid production has continued strong, with the major contribution coming again from Japanese workers. Yamada and Hirose (34C) isolated a new bacterial strain capable

of producing both glutamic acid and alanine, as well as two other strains producing only alanine. Wakisaka and others (33C)screened over 20,000 microorganisms for glutamic acid production. Chibata and others (72C) screened 60 strains of bacteria, actinomycetes, and molds in various media for their ability to produce isoleucine. The screening method whereby Micrococcus glutamicus was isolated and selected was described by Udaka (32C). Microorganisms isolated from soil environments in close proximity to soybean roots were examined by Becker and Schmidt (IOC) for their ability to produce amino acids. The intracellular lysine, methionine, and tryptophan content of 271 strains of yeast were examined by Nelson and others (26C). Lysine yields up to 60y0 of the total cellular nitrogen were found. The free amino acids of eight different molds were studied by Close (I3C). The pathway of diaminopimelic acid (DAP) biosynthesis in a variety of microorganisms was reviewed by Gilvarg (76C). A very thorough study of the production of DAP in submerged culture by a n Escherichia coli lysine-dependent auxotroph was carried out by Angulo (7C). Both chemical and microbial methods for producing glutamic acid were reviewed by Kretovich and Yakovleva (22C). Specific reports on diaminopimelic acid, glutamic acid, lysine, and tryptophan formation by various microorganisms are summarized in Table 111. The complete review contains reports on other amino acids as well.

Antibiotics Considerable efforts were again devoted to methods of improving anti-

Table

II.

Citric Acid

Fermentation

Investigation Surface Culture Two strains capable of 68 and 76y0 yields 5 % methanol in absence of Cu and Mn, pH 1.7-1.9, 66% yields 3% KpSOa increased yields in various molasses 10 to 30% 3% K2S04 permitted increasing fermenting depth from 8 to 13 cm., same conversion efficiency Submerged 5% methanol improved citric acid yield, but not as much as in stationary culture 3% methanol before inoculation stimulated citric acid production from cane molasses Reducing Fe, Mn content of molasses media by pretreatment with superphosphate, lime, KP(FeCN4) Production of citric acid in medium containing 5-75 p.p.m. Cu Patent

VOL. 53, NO. 1 1

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NOVEMBER 1961

Ref.

(10B) (ZZB)

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(sun) W5B) ($1B )

(27B)

(Z4W

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a n r a Unit Processes Review biotic production and searching for new antibiotics. Also, progress has continued i n gaining a better understanding of the biosynthesis of various antibiotics. This latter progress, as well as reports and patents of new antibiotics, is summarized in the complete review. Some of the process improvements and publications dealing with longer established antibiotics fermentations are summarized in Table IV. Others are included in the complete review. Of particular note here are the production of 6-aminopenicillanic acid and new penicillins derived from it. Another highlight is the report by Herold and others ( 3 5 0 ) of chlorotetracycline yields of 5 grams per liter and penicillin yields of 7000 units per ml. These are the highest yields reported in the literature to date.

Vitam ins Carotene. Interest continues in the possible utilization of microorganisms containing intracellular carotene as a source of provitamin A for animal feeds.

Table 111. Amino Acid

Diaminopimelic PAP)

Glutamic acid

Lysine

Trypotophan

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A patent was issued to Nakamura and others (7OE) for a process in which carotene is directly synthesized in and separated from the mycelia of a Penicillium species grown in a methyl radicalcontaining nitrogenous medium a t a p H less than 3.0. Production of carotenoid pigments by four halophilic bacteria was studied by Baxter ( I E ) . Dispersed mycelial growth of Choanephora trispora, a mold rich in carotene, was obtained by Zajic and others (27E) by supplementing the medium with carboxymethylcellulose and agar to increase its viscosity. Ciegler and others (ZE) demonstrated that the stability of carotene in dried fermentation solids is enhanced by the addition of antioxidants during or after fermentation. Riboflavin. Two Czech patents were granted for riboflavin processes employing Eremothecium ashbyii. Hanus and others (5E) patented a mixed culture fermentation with Streptomyces aureofaciens, yielding a product for fodder enrichment containing both chlorotetracycline and riboflavin. This process obviates the need for strict asepsis.

Amino Acid Production by Microorganisms

Micoorganism

Comments

Evaluation of carbon sources showed combination of sucrose and glycerol optimum for good rate, high yield. Used alone, monosaccharides gave better yields than disaccharides; fructose gave fastest DAP accumulation rate Sucrose stimulates DAP biosynthesis Pleomorphism related to period of high DAP production rate Patent Bacillus giganfeus Medium containing carbohydrate, urea, Ca salt Brevibacferium divari- 45% yields based on glucose consumed in 150-,15,000-gal. fermencatum tors Microbacterium sali40% yields based on sugar consumed cinovorum by new species isolated from sewage Brevibacterium Zacto- Production by new species f ermenfas High concn. of nitrogen source added Aspergillus ferreus after initial fermentation Preparation from a-ketoglutarate in Yeast presence of lipide solvent Aeromonas sp. Medium contains a-ketoglutarate in addition to nitrogen source 15 different bacterial Mineral salts medium containing yaminobutyric acid species Pseudomonas sp., Medium contains r>-a-hydroxyglutarate Aeromonas sp. Bacillus megafhuium, Patent B. cereus Production, along with diaminopimelic E. coli acid, in medium containing 0.1-0.5 gram/liter of lysine Flavobacterium f u s Production from a-ketoglutaric acid using transaminase activity of precum, F . breve, Achromobacfer viously grown microorganism Ziquefaciens Micrococcus glufPatent amicus Enferobacferiaceae sp. Patent Yeast Preparation from 5-formyl-2-oxovaleric acid E. coli Patent Escherichia coli

INDUSTRIAL AND ENGINEERING CHEMISTRY

Hanus and Munk (4E) patented a fermentation utilizing bone meal as a source of nitrogen and minerals with periodic addirion of sugar. Cyanocobalamin. A number of discoveries of microorganisms capable of producing vitamin BlS were reported during the past year. Three bacterial groups isolated from Bla rich sewage sludge were found by Neujahr (72E) to be vitamin producers. They included Clostridia, methane bacteria, and sulfate-reducing bacteria. I n a n enrichment culture predominated by Methanobacterium omelianskii, Teujahr ( 7 ?E) found activity of 15 pg. per ml., and a Clostridium strain in pure culture was found by Neujahr and Rossi-Ricci (73E) to produce 60 mwg. per ml. of the vitamin. Ostrowski (74E) carried out biosynthesis of radioactive BIZ using Thiobacillus thioparus. Vitamin B12 concentrations of 3 to 4 pg. per ml. were obtained from Rhizobrium melilotis by Johan and others ( 6 E ) . Growth of this bacterium and consequent B12 activity decreased markedly with a n increase in sterilization time. Kitahara and others (8E) reported on B12 accumulation by Lactobacillus delbrueckii, and Kanzaki and others (7E) discussed production of this vitamin by S. humidus, Tanner (79E, 2OE) obtained patents for Bl2 production by Penicillium lilacillum and Botryotrichum atrogriseum. Another patent for a BIZ fermentation, using members of the family Rhizobiaceae cultured in a malt sprouts medium containing more than 0.170 of a quaternary ammonium compound, was granted to Stern (78E). A patent was issued to Speedie and Hall (77E)for a B12 fermentation employing strains of Propionobacter grown initially anaerobically and followed by contact with oxygen. Grant ( 3 E ) obtained a patent for increasing the B12 content of Propionobacterium freundenreichii broth by vigorous oxygenation following initial anaerobic growth. Perlman and others (75E)were successful in extracting the cyanocobalamin coenzyme from cells of various Propionobacter strains. Ascorbic Acid. In a Czech patent, Liebster ( 9 E ) described the production of 2-keto-1-gulonic acid by a Pseudomonas strain acting on calcium I-idonate in a mixture of this chemical in solution with calcium d-gluconate. Shoemaker (76E) received a patent for oxidizing I-idonic acid or its salts to 2-keto-lgulonic acid using a mixed culture technique.

Steroids Interest in microbial steroid transformations remained high, as evidenced by the reported continued large-scale screening of microorganisms. These

a

Table IV. Antibiotic Actinomycins

Amphotericin

Microorganism Comments Fermentation of Streptomyces actinomycin C chrysomallus complex Fermentation of actinomycins F1 and F3 Streptomyces Patent

Antibiotic Griseofulvin

Neomycin

Bacitracin

Nisin Novobiocin

SP.

Chlorotetracycline

Colimycin

Cycloheximide Demethyltetracycline Dihydrostreptomycin Erythromycin

Fumagillin

Supplementation of Streptomyces aureofaciens medium with 2010 p.p.m. nicotinic acid or 8-10 p.p.m. 3-indolylbutyric acid Pasteurized medium, 10-15 mg./liter of antibiotic added prior to fermentation, without aseptic conditions Increasing antibiotic production by adding fluoride to medium 5’gram/liter in 6065 hr. by P level control 1.5% soybean meal in place of 0 . 5 % corn steep liquor increased starch concn. from 1-3%, yield increased from 0.25-1.0 gram/liter Streptomyces Patent naracensis Streptomyces Mutant strain aureofaciens Direct fermentaStreptomyces humidus tion production Streptomyces Effect of temperature on antibiotic erythreus yield interrelated with strain, medium comp., other conditions Characteristic pattern of organic acid occurrence, pH reducing nature of medium, antibiotic production as affected by phosphate concn. and natural oils Low antibiotic production in glucose or maltose, high production in starch, associated with different morphological character of hyphae

r

d Unit Processes Review

Production of Antibiotics

SP.

Antibiotic producBacillus lichenifor mis tion concurrent with spore formation; 24-hr. fermentation Biomycin Feed supplement Actinomyces rich in biomycin aureofaciens and vitamin Bu Cephalosporin C Cephalosporium Patent

n

Nystatin

Oleandomycin Oligomycin

Oxytetracycline

Microorganism Comments Penicillium Medium initially patulum low in carbohydrate ; carbohydrate is added after 20 hr. Medium containing 3-8y0 soybean meal, 1-4y0 readily assimilable carbohydrate, at least 3% slowly assimilable polysaccharide Streptococcus Milk medium tactis Streptomyces 2.8% glucose, 4% niveus distillers solubles medium influenced by effective aeration and concn. of nitrogen source Streptomyces Addn. of hydroxyspheroides benzoic acid derivatives as precursors to fermentation Streptomyces Basic medium [4% noursei glucose, 0.4% NHaCl or 0.5% NHaNOa, 0.870 CaC03, 0.5yo corn steep liquor (dry basis)] influenced by phosphate concn., aeration, age of inoculum Streptomyces Patent antibioticus Aspergillus 60-gal. pilot plant fumigatus, fermentors ; Glomerella antibiotic isolacingulata tion described Actinomyces Growth and antirimosers biotic formation two distinct phases ; nitrogen, carbohydrate, phosphorus required during growth phase ; exhaustion of inorganic phosphorus, presence of carbohydrate necessary for antibiotic formation Streptomyces New species vendargus Lactic acid medium Streptomyces rimosus increased production; other organic acids have lesser but similar effects in oilcontaining medium Supplementation of medium with 2070 p.p.m. nicotinic acid or 8-10 p.p.m. 3-indolylbutyric acid

VOL. 53, NO. 11

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NOVEMBER 1961

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Unit Processes Review

an 4-

An tibioti c

Penicillin

Ristocetin B Spiramycin

Streptomycin

Table IV. Coninleiits

Production of Antibiotics (continued) Ref. Antibiotic Microorganism Comments Penicitlium Yields of 7000 (%D) Streptomycin Streptomyces Unsterilized chrysogenum units/ml. in 130griseus medium, anti150 hr. by inbiotic added prior tense aeration to fermentation and continuous Medium containing sucrose addn. Congo red which Structure and sta- (280) precipitates antibility of 6-APA biotic during fermentaTetracycline Genus Strepto- Medium containing tion; effect of myces various azole, precursor, importhiazole comtance of intense pounds aeration Streptomyces Production free of Preparation of 6(130) psammoticus other tetracyA P A by direct clines, even in fermentation halogen-containProduction of 4(110 ) ing media; 3.5 carboxy-A\7-butyl grams/liter yields penicillin in 90obtained in liter fermentors peanut meal, Production of new (SD) corn steep liquor, penicillins by glucose, mineral reacting anhydrides salts medium, of acids of general glass fermentors formula Rz(R1)Streptomyces New species Streptomyces Production of N(R3)CH(CH)nCOZHwith 6aureofaciens tetracycline by A P A for short chlorotetracyclineperiod in ferproducing micromentation broth organism via Resynthesis of new (YBD) addn. of 10-100 penicillins from p.p.m. Z-merenzymatically capto-4,S-dicleaved penicillins methylthiazole Nocardia Cerelose, molasses ( 2 0 , 2 0 ) to medium lurida peptone medium Tetracycline proStreptomyces Medium containing ( 4 9 0 , 5 0 0 ) duced instead of am bofaciens ammonium salt chlorotetracycline and various ions in synthetic yields spiramycin medium containI ; medium coning very low taining propiochloride concn. nate or acetate ChlorotetraMedia containing yields spiramycin cycline-prothionalide or I1 ducing compounds havStreptomyces ing thiourea Patent (480) Streptomyces Ash content of soy- (5'4D) nucleus SP. griseus bean meal serves Genus Strepto- Inhibition of chloimportant mineral myces rination in requirement for chlorotetragrowth cycline-tetracycline ferAddn. of 20-70 (610) p.p.m. nicotinic mentation by acid or 8-10 addition of thiop.p.m. J-indolylformamide and butyric acid to pyridazine demedium rivatives Microorganism

results are summarized in the complete review. Comprehensive reviews of the various microbial transformations of steroids were presented by Bowers ( I F ) and Stoudt (78F). Also, Neher (77F) reviewed the chemistry of the corticosteroids. Some studies of specific transformations by various microorganisms are summarized in Table V. Others appear in the complete review.

Enzymes Interest in enzymes is increasing. Among the reviews on this subject appearing in 1960 are those of Beckhorn (7G), on the production of plant and animal enzymes; Sivolap (8G) on production and application of enzymes in

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the Soviet industry; and Halvorson (ZG), on the process of controlling enzyme biosynthesis in yeast. During 1960, patents were issued for a process scheme for preparing enzyme in a solid dry state from a n aqueous extract (SG) and for a n automatic mechanized production of amylolytic molds by surface culture (5G). Processes for enzyme transformation of steroids (3G) and for fixation of nitrogen (6G, IUG) were also described. From a process design point of view, there was a n interesting study by Kalashnikov and others (4G) which described ways of estimating, as well as eliminating, excess physiological heat in enzyme production processes. A comprehensive summary appears i n the complete review.

INDUSTRIAL AND ENGINEERING CHEMISTRY

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Cell Tissue T h e reports concerning the production of cell tissue have been numerous. A list of cell types and species studied during 1960 appears in the complete review. Reviews on this subject of particular note are those of Moser (3H) on culture of mammalian cells, Nickell and Tulecke (4H) on the submerged growth of cells of higher plants, and Martignoni ( 2 H ) o n problems of insect tissue culture. Two reports of interest from a n industrial point of view are those concerning large scale culture-2000-gallon lots of mushrooms (7H) and 5-liter lots of monkey kidney cells ("--by submerged techniques similar to those used in the fermentation industry,

a n w b Polymers

A pilot plant process for directly fermenting clinically sized dextran in 43% of theoretical yield, employing a Streptococcus sp., was described by Rogovin and others ( 6 4 . Both fermentation and isolation equipment are described in detail. According to a patent granted to Behrens and Ringpfeil (ZJ), dextran of molecular weight less than 60,000 can be produced by Lewonostoc mesenteroides if 0.1 to 1Oyo glucose, fructose, or maltose is added to the medium. Malek and Lacko ( 5 4 patented a dextran process in which 5 to 10% of the broth following the fermentation is used as inoculum for fresh sterile nutrient. This cross inoculation procedure can be repeated upward of 10 times. Commercial interest has been indicated in phosphomannan (U), a polymer produced by some yeasts. Shake flask studies of phosphomannan production from glucose in 50 to 55% yield using strains of Hansenula holstii were described by Anderson and others (7J). A patent has been issued for this process ( 3 4 .

Gibberellins T h e sources, structure, and uses of gibberellins were featured in a 17-report symposium sponsored by the AmerSix ican Chemical Society ( 6 K ) . different strains of Gibberella fujikuroi and its conidial phase, Fusarium moniliforme, were shown by Ricicova and others ( 4 K ) to have vast differences in their abilities to produce gibberellin. Highest yields obtained in a 14-day shake flask fermentation in a sucrose-corn steep liquor medium were 240 mg. per liter. I n a study of carbon and nitrogen sources, Perez (3K) found that best yields (80 to 90 mg. per liter) were obtained in glucose-(NH4)3P04 and sucrose-asparagine media. Sanchez-Marroquin and others ( 5 K ) found a molasses-corn steep liquor effective for gibberellin production. Lerzedello and Whitaker (2K) studied the effect of sucrose level, maintained by continuous feeding, on product yield. Dietrich (7K) p a t e n k d production of gibberellins in sufite waste liquors and wastes from various fermentation and dairy processes.

Insecticides A comprehensive review of crystalliferous bacteria and their application as commercial insecticides was prepared by Heimpel a n d Angus (2.L). O n e commercial process for the production of Bacillus thuringiensis spores in 12,000gallon carbon steel fermentors was described in detail by Gemmill and Robbins ( 7L). Krieg and Mueller-Koegler (3L) reported that certain mold contaminants

Table V. Transformation 1-hydroxylation of 9-halopregnanes 16a-hydroxylation of 901fluorohydrocortisone

Unit Processes Review

Microbial Transformation of Steroids Microorganism

Comments

Genus Morfierella

Patent

Streptomyces reseochromogenes

Conversion of 0.5 gram/ liter to triamcinolone in 84% yield; Fe-induced reversion Mixture of prednisolone and A*-20@-hydroxy compound S formed Patent

1.2-dehydrogenation and 1I@- Pseudomonas sp. hydroxylation of Reichstein’s compound S 1,2-dehydrogenation of Flavobacterium sp., steroids Streptomyces sp. 1,2-dehydrogenation of 20Bacterium cyclo-oxidans, Patent dehydropregnanes Corynebacterium simplex, Mycobacterium rhodochrous 28-hydroxylation of deoxySclerotinia libertiana Combinations of 2p,llP,corticosterone and corticoslS@-hydroxyderivaterone tives 68-hydroxylation of digiTricothecium roseum 15% yield in 48-hr. contoxigenin version period 7a-hydroxylation of androsDiplodia natalensis Patent tanes and pregnanes 1la-hydroxylation of tigogenin Rhizopus nigricans, Product converted in 3-keto derivative Aspergillus orchraceus three chemical steps to 17a-hydroxy-Sa-pregnane-3,11,20-trione 1la-hydroxylation of progesRhizopus nigricans Conversion of up t o 8 terone grams/liter, 70% yield 1la-hydroxylation of progesAspergillua ochraceus Conversion of up to 50 terone grams/liter, 90% yield lla-hydroxylation of 1l-desGenus Fusarium Patent oxy-17-hydroxy corticosterone and A1 and/or A8 derivatives lla- and llp-hydroxylation of Corticium sasakii Mixture of hydrocortiReichstein’s compound S sone, epi-isomer, monohydroxylated compound Absidia orchidis Mixture of hydrocortisone, epi-hydrocortisone lla- and llp-hydroxylation of Cunninghamella bainieri Ratio of or to @ product, Reichstein’s compound S influenced by, and 6aand derivatives C1 function 118-hydroxylation of steroids Rhodosepforia sp. Patent 1 la,l7a,-dihydroxylation of Dacfylium dendroides Patent 16a-alkyl-4-pregnane-3,20or-diones 12-hydroxylation of 9(11)Organisms capable of Patent dehydrosteroids 1I-hydroxylation of steroids with saturated C rings 15-hydroxylation of progesHypholoma sp., Bacillus Patent terone megatherium 158-hydroxylation of steroids Bacillus megatherium Patent l7a-hydroxylation of steroids Genus Trichothecium Patent Preparation of Pa-halo-1 16Cylindrocarpon radicicola Patent hydroxy- and h-halo, 11ketoandrostenediones from corresponding substituted progesterones

in this fermentation completely inhibit the growth of Bacillus thuringiensis.

Other Products Sections dealing with 2,3-butanediol, hydrocarbons, alkaloids, and miscellaneous products appear in the uncondensed review.

Microorganisms Maintenance. A review article by Lincoln (73M) devoted solely to control of stock culture preservation and inoculum building in bacterial fermentations appeared during 1960. I n this article, various techniques were discussed for propagating stock cultures

in a manner that would minimize genetic changes. Specific techniques for preserving stock cultures of particular microorganisms have also been reported. These include sand culturing of Clostridium acetobutylicum ( 77M), lyophilizing Brucella melitensis (IOM), deep freezing Streptomyces cultures (79M), suspending Penglycerol and icillium chrysogenum in 1 0 0 ~ o storing a t 5’ C. ( 6 M ) , freezing of Xanthomonas phaseoli in glycerol broth and storing a t -20’ C. (ZOM), and preparing bacterial spore extracts by use of a colloid mill (75M). O n e study dealt with methods for maintaining algae cultures ( 78M). VOL. 53, NO. 11

NOVEMBER 1961

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a n r a Unit Processes Review Strain Development. From a n economic point of view, strain development is the most important aspect of fermentation process development. Here, major increases in the financial return of a fermentation process can be realized through improving product yield of the fermenting strain. Various techniques for achieving higher yield strains through induced mutation or selection have been described. Included among these are enrichment techniques for isolating Actinomycetes producing antifungal antibiotics (75M), as well as methods for inducing bacterial mutation through selective exposure to penicillin ( 8 M , 7 1 M ) , heat (TIM), ultraviolet rays ( I M , 4 M ) , x-rays ( I M ) , ultrasonic waves ( 7 M ) , shortwave diathermy ( 7 M ) ,HNOz (31W), ethylenimine ( IiM), gamma irradiation through growth on sulfur-35-containing medium (ZiW), and electric shock ( 5 M , 9 M ) . I n the latter, mutation was accomplished by dissipating 100-kw. electrical energy per milliliter of microbial suspension over sufficient time to exceed 10 cal. per ml. and such that greater than 10% of the organisms were killed. Methods for improving the fermenting power of yeasts ( 1 2 M , 14M) have also been described.

Process Equipmeni Fermentor Design. Conventional and novel equipment used for batch fermentation, as well as various laboratory equipment used for continuous cultivation, was reviewed by Elsworth (6iV). A 20-liter fermentor especially designed for continuous antibiotic fermentation was described in detail. Other laboratory equipment for fermentation study included a n air-lift bottle described by Ghosh ( 8 N ) ; a fermentor with a pulsating aerator to minimize foaming, described by Heden and others (72A'); and a continuous feeding device for continuous flask cultures, described by Bulder (LV). Fermentation equipment for vinegar production has been described by Allgeier and Hilderbrandt (1A'). A 6-foot-diameter horizontal fermentor, with a n internal combination aerating and stirring mechanism: and a verticle 3-foot-diameter jet aerated fermentor were described by Zaretskaya ( 2 6 N ) . Based on actual fermentation tests in a mold fermentation, oxygen absorption rates were low in both units. A patent was issued to Rinderer ( 7 9 N ) for a horizontal device with internal agitation and aeration for cultivating microorganisms. Large scale equipment for cultivating Aspergillus oryzae on wheat grits was described by Sergeyeva (2O:V). T h e methods of grit sterilization: air filtration, and incubator disinfection, filling, and ventilation were discussed.

940

Instrumentation. Progress has been made in instrumentation of fermentation operations. This has been discussed in general by Fuld (7N), in alcoholic fermentations by Hichiji (73:V), and in brewing by Trearchis (23:V). Antifoam control by automatic capacitance- and/or inductance-indicating devices has been the subject of at least two studies ( 3 N , 76iV). One report (4lV) has described a foam control system consisting of a jet-baffle arrangement with liquid return to the fermentor. Electrode assemblies withstanding repeated steam sterilization have been used routinely for measurement and control of p H in pilot and plant fermentations (5N,77115 24iV, 2.5N). Measurement and control of the oxidation-reduction potential (ORP) of fermentation brorhs and activated sludges by amperometric means have been discussed in several reports ( 1 7AV, 73N, 17AV, 78J\T, 27Y, 22iIr). Most instruments consisted of polyethylene-covered platinum and gold or antimony electrodes. Ll'ith the advent of successful O R P measurement, attention has begun being focused on the significance of these measurements in a fermenting medium ( 17N). Several reports (gAV, 7 O X ; 27;V) have described the use of the Autoanalyzer for continuous assay of protein, phosphate, reducing sugars, and antibiotics as a possible means of controlling fermentation processes. Other fermentor controls that have been described in the literature include that for temperature (74N)and density (7521').

Sterile Techniques Asepsis. T h e search for ways to improve sterile techniques in fermentation operations is continuing. Aquarone (ZP)has studied the influence of penicillin and tetracycline as contamination inhibitors in alcoholic fermentations. Drublianez (7OP)has studied the occurrence of Schizosaccharomyces pombe in hydrolysis and in alcohol plants. I n some hydrolysis plants, Schizosaccharom p s withdraw completely following a n initial infection. Brunner ( 5 P ) has described, in general terms, disinfection procedures and use of disinfectants in the brewing industry. Air Sterilization. No significant developments appeared during 1960 concerning methods of air sterilization. T h e theory of air sterilization by filtration was reviewed by several workers (7P, 74P). One pilot test ( 7 P ) was reported concerning operational characteristics of air filters. Several reports (3P, ZIP) were concerned with equipment and techniques for characterizing the efficiency of air sterilization devices. Other methods for sterilizing

INDUSTRIAL AND ENGINEERINGCHEMISTRY

air were described (23P); however, it still appears that filtration is the most common and practical method of sterilizing air on a large scale. Media Sterilization. Various methods of media sterilization and the problems associated with each have been discussed in two reviews (77P, 22P). Both cite the lack of microbial death rate data a t high temperatures. Limited data for low temperatures appeared in two reports (75P57 6 P ) . High temperature-short time (HTST) heating appears to hold greatest industrial promise as a practical means of media sterilization. Techniques and equipment for accomplishing this by steam injection heating (ZUP, 25P), and plate heat exchangers ( 4 P ) have been described. The flow and heat transfer characteristics of plate exchangers have been studied in detail by certain university workers (19P, 26P): who visualize wide adaptation of plate heat exchangers in the pharmaceutical as well as the food industries. Sterilization of media by chemicals such as HzOz (27P), p-propiolactone (73P> 24P), ethylene oxide ( 7 3 P ) , propylene oxide (18P), and other sterilants ( 8 P ) has been reported. Sterilization of tissue culture media on a small scale by application of membrane filters ( 7 1P) and depth filtration (gP, 72P) has been reported. These methods are of doubtful application to large industrial fermentation processes, Note has been made (GP) of more rapid and certain sterilization of filled fermentors on autoclaving by a venting technique.

Mass Transfer and Scale-Up Fluid Properties. The rheological character of broths from nystatin, penicillin, streptomycin, and steroid hydroxylating fermentations was examined by Deindoerfer and West (724). Characteristic periods on non-Newtonian behavior were noted during the course of nystatin and streptomycin fermentations. The same authors (704, 174) also reviewed fermentation rheology and its engineering and analytical significance. Broth consistency, as characterized by a rheological index established in a paddle viscosimeter, was found by Carilli and others ( 6 Q ) to be the most important factor affecting aeration efficiency in several mycelial fermentations studied. T h e morphological character of mycelia significantly influenced broth consistency. Charm (74) presented equations for determining the rheological properties of non-Newtonian fluids from capillary and rotational viscosimeter measurements. The equations, however, require previous knowledge of the rheological character OC the fluid for their valid application.

anI-4 Mass Transfer. T h e annual review by Wilke (I/EC, p. 441, May 1960) included sections on gas absorption and interfacial resistance. In a fundamental approach to the analysis of oxygen transfer in fermentations, Deindoerfer and Humphrey (SQ) determined instantaneous mass transfer coefficients for pure gas bubbles rising individually in a water-filled column. T h e coefficients varied with bubble size, as well as with time of existence. The latter finding indicates that a bubble larger than 3 mm. in diameter does not attain steady-state internal circulation within 6 seconds’ existence. Therefore, the Higbie penetration model appears inapplicable to bubbles of this size. Mass transfer coefficients for bubbles rising in a shear field were measured by Timson and Dunn (344). Shear increased mass transfer and decreased ascension velocity. T h e addition of surface active agent decreased the mass transfer coefficient as much as 67%. Oxygen transfer within mold pellets was discussed by Kodama and others ( 7 9 4 ) . T h e importance of this type of intramycelial mass transfer in submerged fermentations was stressed by Donovick (734). Aeration. T h e various systems used in aerating fermentations, as well as fundamental definitions and methods used for measuring oxygen demand and supply were reviewed by Gaden (75Q). Using a horizontal rotating fermentor to study oxygen transfer through a known interfacial area, Phillips and others ( 2 8 4 ) obtained a direct linear relationship between peripheral velocity and oxygen transfer. The efficiency of a jet aeration device was discussed by Boika and others (5Q). T h e energy consumption required for aeration approximated that required for mechanically agitated sparged systems. Sulfite oxidation was used to establish relationships between various mechanical factors and rates of absorption in several types of contactors, including stirred tanks, by Yoshida and others (364). I t was shown that when agitation is poor, the sulfite oxidation rate is controlled by factors other than liquid film resistance. Hyman and Van den Bogaerde (7SQ) evaluated the oxygen transfer capacity of two bench-scale reactors using air oxidation of Na2S04. T h e effects of impeller speed, air flow rate, and various geometrical factors were determined. An empirical relationship was established between the surface area of bubbles and the physical properties of the gassed system in a stirred bench-scale reactor by Boika and others (4Q). Nonhomogeneity in the distribution of dissolved oxygen in a bench-scale Penicillium fermentation was found by

Phillips and Johnson (264, 274). T h e apparent critical dissolved oxygen concentration in the fermentor was higher than determined for the mold. Better agreement was obtained between apparent and actual critical dissolved oxygen levels for a bacterial fermentation carried out in the same fermentor. Also, a more uniform dissolved oxygen level was found throughout the fermentor. Assuming that gluconic acid format i m is proportional to the amount of oxygen transferred, Tsao and Kempe (324, 334) developed empirical correlations based on this biological method for the oxygen transfer rate as a function of agitator power input, air flow rate, and air hold-up in Penicillium chrysogenum and Pseudomonas ovalis fermentations. Phillips and others ( 2 9 4 ) observed that the cell population was decreased and oxygen consumption depressed by addition of several antifoaming agents to a Torulopsis utilis fermentation in which oxygen is the growth limiting nutrient. A rotating-brush platinum electrode was used by Carilli and others ( S Q ) to measure dissolved oxygen in yeast, penicillin, tetracycline, and citric acid fermentations in pilot plant scale fermentors. Sufficient aeration, as indicated by excess dissolved oxygen, could always be achieved a t power inputs of 0.5 to 0.75 hp. per 100 gallons and air flows of 0.3 to 10 volume per volume of fermentation broth per minute in all fermentations. Polarographic measurements using a rotating platinum electrode in a cell mounted in a recirculating leg were described by Lemp (204). This system can be used to determine oxygen demand rate, as well as dissolved oxygen concentration. T h e system was applied to a bench scale Serratia marcescens fermentation. Gondhalekar and Phadke (76Q) determined dissolved oxygen in several penicillin fermentations and found lower levels when the strain employed produced pellet mycelia than when filamentous growth occurred. Aeration of cultures of Escherichia coli and Staphylococcus aureus by Heden and Malmborg (77Q) at pressures exceeding 70 p.s.i.g. caused growth inhibition. Free radical formation was suggested as a possible explanation for this toxic effect. Mixing. T h e annual review by Rushton (I/EC, p. 543, June 1960) included sections dealing with gasliquid contacting, flow patterns, continuous flow reactors, and non-Newtonian fluids. T h e effects of mixing variables on gas-liquid contact, liquidsolid contact, and blending in fermentations were reviewed by Oldshue (254).

Unit Processes Review

T h e importance of the rheological character of the broth with respect to the role eddy size, distribution, and deterioration play in affecting dissolved oxygen homogeneity was pointed out by Deindoerfer (8Q). Laminar and transistional flow patterns for a Newtonian and pseudoplastic liquid in a bench-scale vessel were compared by Metzner and Taylor (274). Shear dissipation decreased more rapidly with distance in the non-Newtonian liquid. At high impeller speeds, however, the pseudoplastic liquid underwent greater bulk flow for a similar power input. Mixing times for acid-base neutralization were determined by Norwood and Metzner (244) in several benchscale vessels. An empirical correlation was determined as a dimensionless Reynolds number plot. Weisman and Efferding (35Q) determined the power required for maintaining an aqueous slurry in suspension and related it empirically with the properties of the liquid and the particles in a dimensionless equation. Mass transfer rates for liquidsolid mass transfer in stirred tanks were related empirically with the Schmidt and Reynolds numbers by Barker and Treybal (74). An organic-in-water emulsion was discussed by Finn (74Q) as a means for characterizing the shear transmitted to surfaces in a liquid under shear. Midler and Finn (22Q) carried out similar studies using the protozoan Tetrahymena pyriformis to characterize shear in stirred tanks in terms of equivalent shear in a rotational viscosimeter device. Scale-up. Changes in power input during novobiocin fermentation were observed by Steel and Maxon (374) to be related to broth consistency and air retention. Differences between pilot plant and plant scale fermentations indicate that differences in mixing between these two scales may be important considerations in scale-up procedures. Bartholomew (24, 34) reviewed scale-up practices in fermentation and pointed out that a suitable compromise had to be made between molal air rates and superficial air velocity in scaling-up. Using identical oxygen transfer rates appears to be the most satisfactory method of compromise and scale-up.

Kinetics and Continuous Fermentation Kinetics. With the development of continuous and highly controlled fermentations there has arisen a need for better characterization of fermentation processes. T h e year 1960 saw several significant advances in the understanding of fermentation kinetics and the development of mathematical models for VOL. 53, NO. 11

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describing such behavior. The status of this knowledge has been reviewed by Deindoerfer ( I IR) . Interesting kinetic models have been proposed by Perret (26R) for a growing bacterial population. by Shu (29R) for product accumulation in microbiological processes, and by Aronoff and Hearon (2R) and Chance and others (7R, 8R) for various metabolic enzyme processes. Nonlinear problems in the mathematical interpretation of kinetic problems of biological systems have been reviewed by Toothill (3711). Numerous investigators have reported experiments on various aspects of microbial kinetic behavior. One such report dealt with measurement of generation lag (79R). Several dealt with the relationship between growth of microorganisms and their rate of supply of energy and oxygen (3R, 4R, 74R, 18R, 23R). One particularly interesting study was that of Borzani and others (3R). These workers demonstrated that the kinetic order of alcoholic fermentation of blackstrap molasses by yeast lay between 0 and 0.5 in the continuous process. Continuous Fermentation. Interest and activity in continuous fermentation have increased considerably. This is evidenced by the sizable Symposium on Continuous Cultivation sponsored by the Society of Chemical Industry, London, in March 1960 (5R, 6R) and the excellent review of continuous cultivation by Malek and Hospodka (22R) containing over 180 references related to this subject. Other reviews include those of Evans (12R), Lumb and Wilkin (20R), Maxon (24R). Wilkin (33R). and Y arovenko (34R). Noteworthy are those by Maxon (24R),for its discussion of multistage fermentation design, and Evans (12R), for its clear explanation of continuous culture theory. Two reviews ( 3 0 4 32R) dealt with the application of continuous fermentation in the brewing industry. T h a t of Stuart and Laufer (30R) is particularly interesting for its discussion of six different processes in use a t the present time. Applications of continuous cultivation techniques to various fermentation processes have been numerous. For example, Polevoi (28R) has cited its use in the production of alcohol from starchy raw materials. Harris and Hajny (14R) have described a pilot plant for continuous glycerol production. Daivson (70R) has carried out continuous fermentation experiments with Succhuromyces rouxii for producing glycerol and arabitol. Prospects for continuous production of lactic acid have been discussed by Arnold and Childs ( I R ) . The production of penicillin by continuous-flow single-, and two-stage fermentation has been presented in an excellent report by Pirt and Callow

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(27R). Jerusalimski ( 7 7R) has cited use of continuous culture in production of yeast, vitamin BIZ, acetic acid, a n d butanol-acetone. Malek (21R) has discussed the application of multistage operation in production of baker’s yeast, conversion of azouracil riboside by Ercherichia coli, and fermentation of sulfite waste liquors by Torulopsis utilis. Yarovenko and others (35R) have discussed the theory of continuous butanolacetic acid fermentation. Detailed reports on the continuous manufacture of baker’s yeast (25R) and beer (13R, 7 4 4 76R) have also appeared. Other products that have been obtained by continuous cultivation techniques include enzymes, organic acids, amino acids, and solvents (9R, 24R, 32R, 33R). I t would seem that almost every type of fermentation process has been investigated for possible adaptation to continuous operation. When problems of handling mycelial suspensions, instrumentation, culture degeneration, and sterility maintenance are more fully solved, continuous fermentation processes should become commonplace. Statistics and Process Design Until recently little attention had been given to the use of statistics in the development of fermentation processes. During 1960, however: three reports appeared on this subject. Fruitful areas to apply statistical methods were found to be those in the design of experiments, identification of key variables, a n d selection of operating conditions that give optimal results. I n a review on the subject, Remmers ( IS) has discussed strategies available in planning experiments to locate optimal conditions. Schultz and others (2s)have described techniques in which a quantitative estimate of variances of different experimental factors can be made, thus allowing one to identify the main sources of variability and to plan fermentation experiments to minimize these effects. Soderberg (3s)has presented a specific application of statistics to yield maximization of a two-step prednisolone fermentation. In this, the optimum level of inhibitor to give maximum yield was determined by an evolutionary operation.

Product Isolation Few significant advances in the technology of fermentation products isolation were reported in 1960. Separation of vegetative and spore cells and concentration of vegetative cells by flotation (72T, 14T) is, however, a new and interesting application of a n old technique. ‘The use of dialysis systems for concentrating microbial suspension dur-

INDUSTRIAL AND ENGINEERING CHEMISTRY

ing growth ( I I T ) holds promise for achieving unusually high concentrations of growing cells. T h e theory and technique for continuous centrifugation in virus processing has been described in detail by Fort Detrick workers ( 7 9 T ) . Studies of fermentation broth filtration have been reported by Urks and others

(31T). A process for separating yeast from liquid media by agglutination of cells with opposite mating types has been patented ( 3 2 T ) . T h e use of chemical reagents such as Tic13 for separating common microbes from their culture media was investigated by Nakamura (76T). Various drying methods such as freeze drying ( 4 T , 17T), spray drying ( 2 2 T ) , and vacuum-heat drying ( 4 T ) have also been studied for possible application in concentrating cellular material. I n certain processes. it is necessary to disintegrate microbial cells before recovery of the desirable product can take place. Two such disintegration techniques that were reported included shaking cells with glass beads (23T) and forcing frozen cells through a small opening under high pressure (6T). T h e use of ion exchange in fermentation processes has been the subject of several studies. Rotman ( 2 4 T ) has reviewed their use in general for microbial processes, Specific ion exchange investigations include selective sorption and purification of vitamin Bl2 ( 7 T , 26T), purification of basic antibiotics ( 8 T ) , separation of the streptomycin complex (IOT. 20T), and recovery of Staphylococcal enterotoxin ( 2 T ) . Other recovery techniques reported include precipitation and purification of carbomycin by liquid aromatic hydrocarbon derivatives ( 9 T ) and of erythromycin by alkali ( Z I T ) , regenerative filtration techniques for recovery of microbial cells ( 3 T ) , and continuous countercurrent extraction of aqueous penicillin solutions (30T) and biological solids ( 2 9 T ) . Also, Bungay and others ( 3 T ) have reported on the use of radioactive tracer techniques in purification process development. T h e development of a vitamin Blz purification process was cited as one successful application of this technique. Isolation and purification processes for various antibiotics have been described. These include antibiotics procephaloduced by Streetomjces sp. sporine (25T), fungicidin (37T),griseofulvin (15T), ristocetin ( I T ) , streptomycin ( 5 T ) , and tetracycline ( 2 8 T ) .

(In),

Waste Disposal At least four reviews (3U, 6G, 7LT, 7 7U) concerning utilization and disposal of wastes appeared in the 1960

a n r R f l Unit Processes Review literature. O n e was concerned specifically with sewage problems in the fermentation industry (3U). T h e others placed emphasis on newer aspects of waste treatment (77U),kinetic characterization of the activated sludge process( 6 U ) , and general wastes problems in the pharmaceutical industries ( 7 U ) . A continuous 4-liter laboratory-scale activated sludge unit similar but not identical to the Bactogen was described (5U). Investigations were concerned with the particular problems of nitrogen and phosphorus removal from sewage effluants by algae (75U), sewage conditioning with sulfur oxidizing bacteria (gU), reduction i n B.O.D. content of brewery wastes by bio-oxidation ( 4 U ) , and treatment of sulfite pulp wastes through anaerobic methane fermentation (74U). Only one investigation was reported on the physiological characterization of wastes. This dealt specifically with penicillin wastes (76U). Several interesting reports have appeared on utilization of wastes through yeast fermentations. These included reports on the treatment of molasses stillage to produce fodder yeast, glutamic acid, betaine, and choline (72U), preparation of cider, beer, vinegar, .pectin extract, and pectin through utilization of apple pomace (8U); preparation from distillery sludge of yeast hydrolyzate high in B vitamins and amino acids ( 7 3 U ) ; and conversion of distillery residual liquids after alcohol distillation to yield baker’s yeast, glycerol, amino acids, and betaine (IOU). Other utilization processes were those of producing vitamin Blz concentrates through secondary fermentation of waste fermentor liquors by a mixed culture derived from sewage sludge ( 2 U ) and saccharification of potato mash by means of a preparation obtained from the waste mycelium of a citric acid fermentation (7U).

Bibliography Solvents

(1A) Calleo, V., Montoya, E., Microbiol. espaii. 12, 193 (1959). (2A) Drews, W., Branntweinwirtschaft 100, 384 (1960). (3A) Filipan, T., Agricultural-Forestry Facultv. Zagreb. 1960. (4A) Gd1; Gdyaye:, S.’P., Russ. Patent 128,828 (.Tu (June 1, 1960). (5A)--Gul ayev, S. P., Spirtooaya Prom. (5A) 26, 10 (I960 6960 . (6A) Ibid., p. 12 (1960). (7A) Harris, J. F., Hajny, G. J., J . Biochem. Microbiol. Technol. Eng. 2, 9 (1960). @A) Honpo, (8A) Hongo, M. (to Sanraku Shuzo Kabushiki Kaisha. Tokvo), U. S. Patent 2,945,786 (July 19, 1960).‘ ‘ (9A) Kakolewski, P., Przemysl Spozywczy 14, 447 (1960). (10A) Konovalov, S. A., Chestnov, P. G., Spirtovaya Prom. 26, 43 (1960). (11A) Kovats, J., Prace Insf. i Lab. Bada-

wczych Przemyslu Spoiywcrego 10, 55 (1960). (12A) Krisnamurthi, B. G., Current Sci. (India) 29, 346 (1960). (13A) Krisnamurthi, B. G., J . Sci. Znd. Research (India) 19C, 255 (1960). (14A) Nakhmanovich, B. M., Shcheblykina, N. A,, Mikrobiologiya 29, 67 (1960). (15A) Nakhmonovich, B. M., Shcheblykina, N. A., others, Latvijas PSR Zindtgu Akad. Vzstis 1960,p. 135. (16A) Polevoi, L. A,, Spirtcvaya Prom. 26, 11 (1960). (17A) Pomar, E., Emiliani, E., 7th Latin American Congr. of Chemistry, 1960. (18A) Shukla, J. P., Pandey, S. N., Kapoor, B. D., “Proc. 28th Conv. Sugar Technol. ASSOC.,” Pt. 11, p. 227,1960. (19A) Sutoh, T., others, Repts. Inst. Agr. Research Tohoku Univ. 11, 115 (1960). (20A) Yarovenko, B. L., Spirtovaya Prom. 26, 3 (1960). (21A) Yarovenko, V. L., Mikrobiologiya 29, 561 (1960). Organic Acids (1B) Abe, S., others, Ann. Meeting Agr. Chem. SOC.Japan, April 1960. (2B) Abe, S., others, J . Agr. Chem. Soc. (Japan) 34, 66 (1960 (3B) Allgeier, R. J., Ikildebrandt, F. M., Advances in Appl. Microbiol. 2, 163 (1960). (4B) Arnold, M. H., Childs, C. G., Mfg. Chemist 31, 333 (1960). (5B Balatti, A,, Ertola, R., Rev. Latin. Am. Microbiol. 3, 25 (1960). f6B) Buendia. M.. Garrido. J. M..’ Rev. ’ denc. apl. ( k a d r i i ) 66, 23 (i959). Zbid., 67, 130 (1959). Buntova, E., Tibenska, M., Mitterhauszerova, L., Biologia 1 5 , 5 1960). Chem. Eng. 67, No. 18, 50 11960) 1OB) Cinerman, A., Chemical Institute “Boris Kidric,” Ljubljana, 1960. (11B) Imsenecki, A. A,, Solnzeva, L. I., Kuranova, N. F., Mikrobiologiya 29, 177

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Tochikura, T., Bull. Inst. Chem. Research, Kyoto Univ. 38, 94 (1962. , , (14B) atagiri, H., Imai, K., others, Bull. Agr. Chem. Soc. (Japan) 24, 163 (1960). (1iB) kinoshita, S., Japan. Patent 10,699(’60) (Aug. 6). (16B) Kobayashi, T., Ibid., 147’(60) (Jan.

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(I%{ * Zbid., 10,694’(60). (18B) Kyowa Hakko Kogyo Kabushiki Kaisha, Fr. Patent 1,197,776 (Dec. 2, 1959). (19B) Leopold, H., Valtr, Z., Czech. Patent 97,291 (May 9, 1960). (20B Zbid., 97,292. (21Bj L obo, F. X., Nadkarni, S. M., Can. Patent 604,531 (Sept. 6, 1960). (22B) Malo, J. L., Regueiro, B., Microbiol. espan. 12, 139 (1959). (23B Zbid., p. 243. (24Bj Miles Laboratories, Fr. Patent 1,223,556 (Oct. 12, 1960). (25B) Noguchi, Y., Bando, Y., J . Fermentation Technol. (Jufan) 38, 485 (1960). (26B) Rhodes, R. A,, others, Bacteriol. Proc. 60th Mtg., SOC. Am. Bacteriologists, Philadelphia, Pa., May 1960. (27B) Schweiger, L. B. (to Miles Laboratories), Can. Patent 593,050 (Feb. 23, 1960). (28B Takano, S., J . Agr. Chem. SOC. ( d p a n ) 34, 214 (1960). (29B Terada, O., others, Ibid., p. 166. (30B] Verbina, N. M., Mikrobzologzya 29, 363 (1960). (31B) Ziobrowski, J., Zmaczynski, K., Pr..emyst Fermentation 4, 99 (1 960).

Amino Acids (1C) Angulo, J., Ph.D. thesis, Faculty of Sciences, Univ. Madrid, October 1960. (2C) Angulo, J., Diaz, T., others, Anales real soc. espaii. j%. y qutm. (Madrid) 55B, f 4C 5 ~ Zbid., / 7 Zp.~705. 759. ~ ~ ~ ~ :

5C Ibid., 56B, 311 1960). (6C Zbid., 56B, 317 11960) (7C] Angulo, J., others, ibid., 56B, 413

(9C) Ajinomoto Co., Belg. Patent 580,453 (July 7, 1959). (1OC) Becker, G. E., Schmidt, E. L., Bacteriol. Proc., 60th Mtg., SOC. Am. Bacteriologists, Philadelphia, Pa., May 1960. (11C) Broquist, H. P., Brookman, J. A. (to American Cyanamid Co.), U. S. Patent 2,965,545 (Dec. 20, 1960). (12C) Chibata, J., Kisumi, M., Ashihaga, Y., J . Biochem. Microbiol. Technol. Eng. 2, 361 (1960). (13C) Close, R., Nature 185, 609 (1960). (14C) Cook, R. C. (to International Minerals and Chemicals Corp.), U. S. Patent 2,933,434 (April 19, 1960). (15C) Doi, S., others, J . Agr. Chem. SOC. ( J a j a n ) 34, 863 (1960). (16C) Gilvarg, C., Federation Proc. 19, 948 (1960). (17C) Good, R. C., Gunsalus, I. C. (to International Minerals and Chemicals Corp.), U. S. Patent 2,927,059 (March 1, 1960). (18C) Good, R. C., Norman, 0. L. (to International Minerals and Chemicals Corp Zbid., 2,945,787 (July 19, 1960). (19C) dhang, H. T. (to Chas. Pfizer & Go.), Ibid.,2,947,666 (Aug. 2, 1960). (20C) Katagiri, H., Tochikura, T. (to Ajinomoto Co.), Ibid., 2,953,499 (Sept. 20, 1960). (21C) Kita, D. A. (to Chas. Pfizer and Co.), Ibid., 2,921,002 (Jan. 12, 1960). (22’2) Kretovich, V. L., Yakovleva, V. I., Izuest. Akad. Nauk S.S.S.R.,Ser. Biol. 2, 197 (1960). (23C) Kyowa Hakka Kogyo Kabushiki Kaisha, Fr. Patent 1,203,355 (Jan. 18, 1960). (24C) Masuo, E., Wakisaka, Y., Ozawa, T., Japan. Patent 12,643’(60) (Sept. 3). f25C) Merck & Co., Fr. Patent 1,221,194 (May 31, 1960). (26C) Nelson, G. E., others, Appl. Microbiol. 8, 179 (1960). (27C) Ogawa, T., Sumida, T., others (to Ajinomoto Co.), U. S. Patent 2,940,903 (June 14, 1960). (28C) Pfizer, Chas., & Co., Fr. Patent 1,207,437 (Feb. 16, 1960). (29C) Zbid., 1,209,342 (March 1, 1960). (30C) Zbid., 1,220,977 (May 30,1960). (31C) Su, Y . C., Yamada, K., Bull. Agr. Chem. Soc. (Japan) 24, 525 (1960). (32C) Udaka, S., J . Bacterial. 79, 754 (1960). (33C) Wakisaka, Y., others, Ann. Repts. Shionogi Research Lab. No. 10, 109 (1960). (34C) Yamada, K., Hirose, Y., Bull. Agr. Chem. Sac. (Japan) 24,621 (1960). Antibiotics (1D) Abbott Laboratories, Brit. Patent 843,560 (Aug. 4, 1960). (2D) Abbott Laboratories, Fr. Patent 1,223,921 (June 7, 1960). (3D) Abilgaard, K. (to Lovens Kemiske Fabrik), Indian Patent 72,629 (1960). (4D) American Cyanamid Co., Brit. Patent 855,159 (Nov. 30, 1960). (5D) American Cyanamid Co., Fr. Patent 1,217,623 (May 4, 1960). VOL. 53, NO. 11

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(6D) Zbid., 1,223,916 (June 7, 1960). (7D) Zbid., 1,232,928 (Oct. 12, 1960). (8D) Aplin and Barrett, Ltd.; Brit.’ Patent 844,782 (April 17, 1960). (9D) Arishima, M., Sekizawa, Y. (to American Cyanamid Co.), U. S. Patent 2,949,406 (Aug. 16, 1960). (10D) Zbid., 2,949,407 (Aug. 16, 1960). (11D) Ballio, A., Chain, E. B.: others, Nature 185, 97 (1960). (12D) Becker, 2. E., Maksimova, R. A., Antibiofiki 5, 27 (1960). (13D) Beecham Research Laboratories, Ltd., Indian Patent 705,50 (1960). (14D) Belik, E., others, Czech. Patent 94,083 (Feb. 15, 1960). (15D) Belik, E., Herold, M., Doskocil, J., Fr. Patent 1,217,612 (May 4, 1960). (16D) Bernlohr, R. W., h-ovelli, G. D., -4rch. Biochem. Biophys. 87, 232 (1960). (17D) Bhuyan, D. K., Ganguli, B. N., Ghosh, D., Hindustan Antibiotics Bull. 2, 107 (1960). (18D) Brinberg, S. I., Antibiotiki 5, 47 (1960). (19D) Bristol Laboratories, Fr. Patent 1,224,022 (June 21, 1960). (20D) Brockman, H., Bohne, A. (to Schenley Industries), U. S. Patent 2,953,495 (Sept. 20, 1960). (21D) Cheney, L. C., Lien, J. (to BristolMyers Co.), Ibid., 2,956,930 (Oct. 18, 1960). (22D) CIBA Ltd., Fr. Patent 1,216,219 (April 22, 1960). (23D) Ibid., 1,217,627 (May 4, 1960). (24D) Zbid., 1,217,628. (25D) Zbid.,1,218,406 (May 10, 1960). (26D) Zbid., 1,218,413. (27D) Darken, M. A., others, Zentr. Bakteriol. Parasitenk. I , 177, 319 (1960). (28D) Dutcher, J. D. (to Olin Mathieson Corp.), Can. Patent 598,125 (May 27, 1960). (29D) Farbenfabriken Bayer A.-G., Brit. Patent 832,032 (April 6, 1960). (30D) Glaxo Laboratories, Ltd., Fr. Patent 1,192,123 (Oct. 23, 1959). (31D) Glaxo Laboratories, Ltd., Indian Patent 70,825 (1960). (32D) Goodman, J. J., Yound, R . W. (to American Cyanamid Co.), U. S. Patent 2,923,667 (Feb. 2, 1960). (33D) Zbid., 2,923,668. (34D) Grabovskaya, 0. Z., Doklady A k a d . Nauk S.S.S.R. 133, 218 (1960). (35D) Herold, M., Sikyta, B., Zajicek, J., 1st Intl. Fermentation Symp., Rome, Mav 1960.

wzssenschaften 47, 474 (1960). (39D) Koninklijke Nederlandsche Gist-en Spiritusfabriek, N. V., Fr. Patent 1;204,303 (Jan. 1, 1960). 40D) Zbzd., 1,220,814 (May 27, 1960). 141D) Larsen . M. H., Peterson, W. H., AppZ. Mzcrobiol. 8, 182 (1960). (42D) Lyn, S., Tun, S., others, Antzbzofzkz 6 53 -,

I-

(ic)m\ \ - , ~ -

(43D) Mil1er:’I. M. (to Merck & Co.), Can. Patent 597,331 (May 30, 1960). (44D) Nakazawa, K., Shibata, M., others (to Takeda Pharmaceutical Industries), Japan. Patent 12,647’(60) (Sept. 3). (45D) hTakazawa, K., Shibata, M., others (to Takeda Pharmaceutical Industries), U. S. Patent 2,931,756 (April 5, 1960). (46D) Naletov, I. F., Sbirtovaya Prom. 26, 28 (1960). (47D) National Research Development Corp., Brit. Patent 847,375 (Sept. 7, 1960).

944

(48D) Ninet, L., Verrier, J., Can. Patent 607,077 (Oct. 18, 1960). (49D) Ninet, L., Verrier, J. (to RhonePoulene), U. S. Patent 2,943,024 (June 28, 1960). (50D) Zbid., 2,943,025. (51D) Orlova, N. V., Zaytseva, Z . M., 1st Intl. Fermentation Symp., Rome, Mav 1960. (5ZD)‘Pfizer, Chas., & Co., Brit. Patent 840,829 (July 13, 1960). (53D) Pfizer, Chas., & Co., Fr. Patent 1,234,124 (Oct. 14, 1960). (54D) Ibid., 1,223,502 (June 13, 1960). (55D) Zbid.,Brit. Patent 832,391 (April 6, I 9617).

(5iDj”Pirt, S. J., Callow, I). s., 1st Inti. Fermentation Symp., Rornc, May 1960. (57D) Popova, L. A,, Antzbiotiki 5, 14 (1960). (58D) Rolinson, G. N., 1st Intl. Fermentation Symp., Rome, May 1960. (59D) Sanchez-Marroqum, A.; 7th Latin Am. Congr. Chem., 1960. (6OD) Smith, C. G.: ApjZ. 1Microbiol. 8, 42 ( 19 60) . (61D) Smolek, K.. others, Czech. Patent 96,751 (September 1960). (62D) Snake J. E., J . Bacteiiol. 80, 552 ( 19 60) . (63D) Takeda Pharmaceutical Industries, Fr. Patent 1,224,015 (June 21, 1960). (64D) Tanchenko, I. M., Savhenko, N. Y., Semernya, V. M., Spzrtovaya Prom. 26, 24 (1960). (65D) Tanner, F. W. (to Chas. Pfizer & Co.), U. S. Patent 2,940,905 (June 14, I9 m

[66D)‘?bid., 2,940,906. 67D) Zbid., 2,940,907. (68D) Zbid., 2,940,908. (69D) Zbid., 2;940,909. (70D) Umezawa, H., others, Japan. Patent 3847’(60). (71D) Vanck, Z . , others, “Proc. Symp. Antibiotics, Prague, 1959,“ p. 143, Artia, Prague, 1960. (72D) Virgilio, A., Hengellen, C., Farmaco (Paoia) Ed. sci. 15, 164 (1960). (73D) Vjsser, J., others. J . Biochem. Microbzol. Technol. Eng. 2, 31 (1960). Vitamins ( l e ) Baxter R. M., Can. J . Microbiol. 6, 417 (1960). (2E) Ciegler. A., Nelson: G. E., Hall, H. H., Bacteriol. Proc. 60th Mtg., Soc. Am. Bacteriologists, Philadelphia, Pa., May 1960. (3E) Grant, D. W. (to Oh-Mathieson Chemical Corp.), U. S. Patent 2,956,932 (Oct. 18, 1960). (4E) Hanus, J., Munk, V., Czech. Patent 97,486 (November 1960). (5E) Hanus, J.; Munk, V., Roubicek, R., Ibid., 95,503 (May 1960). (6E) Johan, B., Szabo Szucs, J., Szabo, I., Acta Microbiol. Acad. Sei. Hung. 7, 391 (1960). (7E) Kanzaki, T., others, Ann. Mtg., Agr. Chem. SOC.,Japan, April 1960. (8E) Kitahara, K., others, Ibid. (9E) Liebster, J., Czech. Patent 96,983 (April 1960). (10E) Nakamura, R., Mase, Y . , others, Japan. Patent 10,999’(60) (Aug. 11). (12E) Neujahr, H. Y., Svensk Kem. Tidskr. 72, 402 (1960). (11E) Neujahr, H . Y., Acta Chem. Scand. 14, 28 (1960). (13E) Neujahr, H. Y., Rossi-Ricci, G., Zbid., 14,43 (1960). (14E) Ostrowski, MT., Postqpy Biochem. 6 , 255 (1960). (15E) Perlman, D., Semar, J. B., Frazier, W. R., Div. Agr. Food Chem., 138th

INDUSTRIAL AND ENGINEERING CHEMISTRY

Meeting, ACS, New York, September 1960. (16E) Shoemaker, R . N. (to Chas. Pfizer 8: Go.), U. S. Patent 2,948,659 (Aug. 9, 1960). (17E) Speedie, J. D., Hull, G. W. (to The Distillers Go., Ltd.), Zbid., 2,951,017 (Aug. 30, 1960). (18E) Stern, R. M. (to Pabst Brewing Co.), Zbid., 2,923,666 (Feb. 2, 1960). (19E) Tanner, F. W. (to Chas. Pfizer & Go.)?Zbid., 2,921,887 (Jan. 19, 1960). (20E) Zbid., 2,932,608 (April 12, 1960). (21E) Zajic, J. E., others, Bacteriol. Proc., 60th Mtg., SOC. Am. Bacteriologists, Philadelphia, Pa., May 1960. Steroids

(1F) Bowers, A,, 3rd Natl. Congr. h4icrobiol., Mexico City, 1960. (2F) Charney, W. (to Schering Corp.), U. S. Patent 2,951,016 (Aug. 30, 1960). (3F) Charney, W.: Herzog, H. L., Sutter, D. (to Schering Corp.), Ibid., 2,958,631 (Nov. 1, 1960). (4F) Dulaney, E. L., McAleer, W. J., Stoudt, T. H. (to Merck and Co.), Ibid.,2,960,434 (Nov. 15, 1960). (5F) Esparza, F., 3rd Natl. Congr. Microbiol., Mexico City, 1960. (6F) Feldman, I,. I., Rigler, N. E., Shay, A. J. (to American Cyanamid Co.), U. S. Patent 2,962,423 (Nov. 29, 1960). (7F) Goodman, J. J. (to American Cyanamid C o . ) , Zbid,, 2,938,834 (May 31, 1960). (SF) Goodman, J. J., Smith, L. L., Apjl. Microbiol. 8, 363 (1960). (9F) Hagiwara, H., J . Pharm. SOC.(Japan) 80, 962 (1960). (10F) Hanc, 0. A , , Capek, A,, Tadra, M., Czech. Patent 95,389 (May 1960). (11F) Kenney, H . E.: Serota, S., others, J . Am. Chem. Co. 82, 3689 (1960). (12F) Kita, D. A. (to Chas. Pfizer & Co.), U. S. Patent 2,936,264 (July IO, 1960). (13F) Mannhardt, H., Metz, H. (to E. Merck A-G.), Ibid., 2,950,226 (Aug. ‘1-

,n,n\

L3) I Y U U ) .

(14F) McAleer. W. J., Stoudt, T. H. Zbid., 2,954,326 (to Merck & Co.), ’ (Sept. 27, 1960). (15F) Murray, H. C., Meister, P. D. (to The . (Feb. 16, IjDiohn I$iO). Go.\. Ibid.,~,2,925,366 , I

(16F) Shirasaka, M.: Tsuruta, M., Arch. Biochem. Biophys. 87, 838 (1960). (17F) Neher, R.; Antibiotica et Chemotherapia 7, 1 (1960). (18F) Stoudt, T. H., Advances in Afifil. Micro6iol. 2, 183 (1960). (19F) Thnma, R. W., Fried, J. (to OlinMathieson Corp.), U. S. Patent 2,955,075 (Oct. 4, 1960). (20F) Zbid., 2,960,436 (Kov. 15, 1960). (21F) Titus, E., Murray, A. W., Spiegel, H. E., J . Biol. Chem. 235, 3399 (1960). (22F) Ccliibayashi, M., Chem. Pharm. Bull. (Tokyo) 8, 255 (1960). (23F) il‘eaver, E. A., Kenney, H . E., Wall, M. E., Aflpl. Microbiol. 8, 345 (1960). Enzymes (1Gj Beckhorn. E. J., W’allerstein Labs. Communs. 23, 201 (1960). (2G) Halvorson, H. O., Ibid., 23, 5 (1960). (3G) Hasegawa. T., Takahashi, T., others (to Takeda Pharmaceutical Industries), U. S. Patent 2,966,444 (Dec. 27>1960). (4G) Kalashnikov, E. J., Lifshiz, D. B., Trainina, T. I., Mikiobioloeiya 29, 899 (1960). (5G) Malcher, J., Hosek, K., Chmelar. V., Czech. Patent 95,314 (May 1960). (6G) Nicholas. D. J. D.. Fisher, D. J., Suture 186, 735 (1960).

a (7G) Siepmann, R., MacDonald, J. C., Can. J . Microbiol. 6, 573 (1960). (8G) Sivolap, I. K., Xbirtovaya Prom. 26, No. 7, 27 (1960). (9G) Snyder, V., Gagan, S. (to Miles Laboratories), U. S . Patent 2,922,749 (Jan. 12, 1960). (10G) Van Evs, J., J . Bacteriol. 80, 355 (1960). Cell Tissue (1H) Block, S. S.,J . Biochem. Microbzol. Technol. Eng. 2, 243 (1960). (2H) Martignoni, M. E., Exfierientia 16, 125 (1960). (3H) Mae;, M.,Zbzd., 16, 385 (1960). (4H) Nickell, L. G., Tulecke, W., J . Biochem. Mzcrobiol. Technol. Eng. 2, 287 (1960). (5H) Rightsel, W. A,, McCalpin, H., McLean, I. W., Zbzd., 2, 313 (1960). Polymers (1J) Anderson, R., Cadmus, M., Benedict, R., Arch. Biochem. Biophys. 89, 289 (25 Behrens, U., Ringpfeil, M. (to V. E. B. W :?:e!k er Bernburg) , Ger. Patent 1,083,021 (June 9, 1960). (3J) Benedict, R. G., Jeanes, A. R., Wickerham, L. J. (to United States), U. S. Patent 2,961,378 (Nov. 22, 1960). (45) Chemurgic Dzg. 19, No. 4,7 (1940). (5J) Malek, J., Lacko, L., Czech. Patent 96,416 (July 1960). (6J) Rogovin, S. P., others, J . Bzochem. Microbzol. Technol. Eng. 2, 12 (1960). Gibberellins (1K) Dietrich, K . R., Ger. Patent 1,081,402 (Oct. 22, 1960). (2K) Lerzedello, A., Whitaker, N., Rev. agr. Piracicaba 35, No. 1, 15 (1960). (3K) Perez, Z., 3rd Natl. Congr. Microbiol., Mexico City, 1960. (4K) Ricicova, A., others, Folia microbzol. (Prague) 5, 181 (1960). (5K) Sanchez-Marroquin, A., Teran, J., Alba, R. M., 3rd Natl. Congr. Microbiol., Mexico City, 1960. (6K) West, C. A., Symp. Gibberellins, Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. Insecticides (1L) Gemmill, A. V., Robbins, M. D., Chem. Eng. 67, 42 (Oct. 3, 1960). (2L) Heimpel, A. M., Angus, T. A., Bacteriol. Rev. 24, 266 (1960). (3L) Krieg, A., Mueller-Koegler, G., Naturwissenschaften 46, 630 (1959). Microorganisms (1M) Alikhanyan, S. I., others, Doklady Akad. NaukS.S.S.R. 136,468 (1960). (2M) Aytoun, R. S. C., McWilliams, R. W. (to Glaxo Laboratories, Ltd.), U. S. Patent 2,938,835 (May 31, 1960). (3M) Behringwerke, A.-G., Marburg/ Lahr, Ger. Patent 1,087,320 (April 4. 1959). (4M) Doudney, C. O., Haas, A. L., Genetzcs 45, 1481 (1960). (5M) General Electric Co., Ltd.. Brit. Patent 845,743 (Aug. 24, 19601. (6M) Ghosh, D., Cha Hindustan Antzbiotacs Bull. 2, 14 (8M) Gorimi, .L., ‘Kaufman, H., Scienct 131, 604 (1960). (9M) Gossling. B. S. (to General Electric ’ C;., Ltd.),’ U. S.’ Patent 2,955,076 (Oct. 4, 1960). (10M) Heckly, R. J., Faunce, K., Elbers, S. S., Apfil. Microbiol. 8, 52 (1960). (11M) Iyer, V., J . Bacteriol. 79,309 (1960).

(12M) Kudriavzev, V. I., 1st Intl. Fermentation Symp., Rome, May 1960. (13M) Lincoln, R. E., J . Biochem. Microbiol. Technol. Ene. 2. 49 (1960). (14M) Masscheleh, C. A,, otkers, J. Inst. Brewing 66, 502 (1960). (15M) O’Connor, R. J., Doi, R. H., Haivorson, H., Can. J . Microbiol. 6; 233 (1960j. (16M) Quadling, C., Zbid., 6, 475 (1960). (17M) Rokusho, B., Saitoh, X., J . Agr. Chem. Sac. (Japun) 34, 942 (1960). (18M) Starr, R. C., Am. J . Botany 47, 67 (1960). (19M) Tresner, H . D., Danga, F., Porter, J. N., Aepl. Microbiol. 8,339 (1960). (20M) Tsao, P. H., Leben, C., Keitt, G. W., Phytopathology 50, 88 (1960). ’

Process Equipment (1N) Allgeier, R. J., Hilderbrandt, F. M., Advances in Appl. Microbiol. 2, 163 (1960). (2N) Bulder, C. J., Experientia 16, 565 (1960). (3N) Bungay, H. R., Simons, C . F., Hosler, P., J . Biochem. Microbiol. Technol. Eng. 2, 143 (1960). (4N) Dawson, P. S. S., 1st Intl. Fermentation Symp., Rome, May 1960. (5N) Dispigno, J. E., Ibid. (6N) Elsworth, R., Progr. Znd. Mzcrobiol. 2, 103 (1960). (7N) Fuld, G. J., Advances in Appl. Microbiol. 2, 351 (1960). (8N) Ghosh, D., Hindustan Antibiotics Bull. 3, 28 (1960). (9N) Gerke, J. R., Ann. N. Y.Acad. Sct. 87. 782 11960). (1ON) Grinfel1,’T. C., McLaughflin, D. J., Kelly, J. M., Ibid., 87, 857 (1960). (11N) Gutmann, F., Moss, F., Lehogzky, I., J. Biochem. Microbial. Technol. Ene. 2, 205 (1960). (12N) Heden, C. G., Pederson, C., Gaden, E. L., Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (13N) Hichiji, S., others, Ann. Mtg. Agr. Chem. SOC.Japan, April 1960. (14N) Hichiji, S., Futai, N., Refits. Fermentation Research Inst. (Japan) No. 18, 37 (1960). (15N) Keefer, C. E., Waste Eng. 31, 24 (1960). (16N) Musilek, V., Sevcik, V., Czech. Patent Appl. PV2868-60 (April 30, 1960). (17N) Rabotnova, I. L., 1st Intl. Fermentation Symp., Rome, May 1960. (18N) Reinheardt, G., Hardwick, W., Ann. N . Y. Acad. Sci. 87, 883 (1960). (19N) Rinderer, F. J. (to American Sterilizer Go.), U. S. Patent 2,952,588 (Sept. 13, 1960). (20N) Sergeyeva, N. M., Spirtovaya Prom. 26, 18 (1960). (21N) Smirnov, S. G., Mzkrobiologiya 29, 142 (1960). (22N) Strohm, J., Dale, R. F., Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (23N) Trearchis, G. P., Brewers Dig. 35, 50 (1960). (24N) West, J. M., Stickle, G. P., others, Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (25N) Yegorov, A. S., Myakota, L. I., Sjirtouaya Prom. 36, 16 (1960). (26N) Zaretskaya, D. I., Ibid., 26, 19 (1960). Y

Sterile Techniques (1P) Aiba, S., others, J. Gen. Apfil. Microbiol. (Tokyo) 6, 15 (1960). (2P) Aquarone, E., Afipl. Microbiol. 8, 263 (1 960).

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a Unit Processes Review

(3P) Batchelor, H. W., Advances in Appl, Microbiol. 2, 31, (1960). 4P Black, B. E., A m . Brewer 93,38 (1960). 5P Brunner, R., Int. Fahrzeitschr. Brau. Garnngs. v. Kaltetechn. 13, 179, 201 (1960). (6P) Bungay, H. R., Hosler, P., Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (7P) Chen, C. T., Tin, S. C., J . Ferrnentation Technol. (Japan) 38, 53 (1960). (8P) Comrie, A. A., J. Inst. Brewing 66, 134 (1960). (9P) Daniels, W. F., Hale, M . B., J . Biochem. Microbiol. Technol. Eng. 2, 93 (1960). (IOP) drublianez, E. E., Mikrobiologiya 29, 906 (1960). (11P) Ehrlich, R., Adaances in Appl. Microbiol..2, 95 (1960). (12P) Hale, M. B., Daniels, W. F., Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (13P) Himmelfarb, P., Read, R. B., Bacteriol. Proc., 60th Mtg., SOC. .4m. Bacteriologists, Philadelphia, Pa., May 1960. (14P) Humphrey, A. E., Advances in Appl. Microbiol. 2, 301 (1960). (15P) Humphrey, A. E., Nickerson, J. T. R., Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (16P) Kells, H. R., Lear, S. A., Appl. Mzcrobiol. 8, 234 (1960). (17P) Kempe, L. L., Adoances in Afifil. Microbiol. 2, 313 (1960). (18P) Klarman, W. L., Craig, J., Phytopathology 50, 868 (1960). (19P) McKillop, A. A., Dunkley, W. L., IND.ENC.CHEM.52, 740 (1960). (20P) Morgan, A. I., Carlson, R. A., Ibid., 52, 219 (1960). (21P) O’Connell, D. C., Wiggin, N. J. B., Pike, G. F., Science 131, 359 (1960). (22P) Robinson, H. B., J . M i l k and Food Technol. 23, 49 (1960). (23P) Rudin, R. W., M f g . Chem. 31, 18 (1960). (24P) Toplin, I., Gaden, E. L., Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (25P) Watanabe, H., J . Fermentation Assoc. 18, 563 (1960). (26P) Watson, E. L., McKillop, A. A,, others, IND.ENG.CHEM.52, 733 (1960). (27P) Wolnak, B., Barrington, L. F. (to Armour and Co.), Can. Patent 608,825 (Nov. 15, 1960).

I1

Mass Transfer a n d Scale-UD (1Q) Barker, J. J., Treybal, R. E., A.Z.Ch.E. Journal 6, 289 (1960). (2Q) Bartholomew, W. H., IND. END. CHEM.52, 60 (1960). ( 3 0 ) Bartholomew. W. H.. Advances in ’ &fil. Microbzol. 2; 289 (1960). (4Q) Boika, I., Zhukovskaya, S. A., Annakova, L. A., Med. Prom. S.S.S.R. 1960, No. 9, 36. (5Q) Zbid., No. 10, 13. f6Q) Carilli. A.. Chain. E. B.. others, ’ lyt Intl. Fermentation Symp.; Rome, May 1960. (7Q) Charm, S., Food Research 25, 351 (1960). (8Q) Deindoerfer, F. H., 1st Intl. Fermentation Symp., Rome, May 1960. (9Q) Deindoerfer, F. H., Humphrey, A. E., Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (lOQ) Deindoerfer, F. H., West, J. M., Advances in Appl. Microbzol. 2, 265 (1960). (11Q) Deindoerfer, F. H., West, J. M., IND.ENC.CHEM.52, 59 (1960). (12Q) Deindoerfer, F. H., West, J. M., VOL. 53, NO. 1 1

NOVEMBER 1961

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Unit Processes Review

J . Biochem. Microbiol. Technol. Ene. 2, 165 (1960). onovick, R., Appl. itiizcrobiol. 8, (’?% E960,. (14Q) Finn,’ R. K., 1st Intl. Fermentation Symp., Rome, May 1960. ( l 5 Q Gaden, E. L., Ibid. (16Q] Gondhalokar, R . S., Phadke, R. S., J . Sci. Ind. Research (India) 19C, No. 8, 183 (1960). (17Q) Heden, C. G.? Malmborg, A. S., 1st Intl. Fermentation Symp., Rome, Mav 1960 i

(18Q) Hyman, D., Van den Bogaerde, J. M., I N D . ENG.CHEM. 52, 751 (1960). (19Q) Kodama, T., others, Ann. Mtg., Agr. Chem. SOC. Japan, April 1960. (20Q) Lemp, J. L., J . Biochem. Microbiol. Technol. Eng. 2, 215 (1960). (21Q) Metzner, A. B.. Taylor, J . S., A.I.Ch.E. Journal 6 , 432 (1960). (22Q) Midler, M., Finn, R. K., Div. Agr. Food Chem.. 138th Meeting, ACS, New York, September 1960. (23Q) Milburn, T. R., Beadle, I,. C.: J . Exptl. Biol. 37, 444 (1960). (24Q) Norwood, K. W., Metzner, A. B., A.I.Ch.E. Journal 6 , 432 (1960). (25Q) Oldshue, J. Y., Adoances in Appl. Microbid. 2, 275 (1960). (26Q) Phillips, D. H., Johnson. M. J., 1st Intl. Fermentation Symp., Rome, . . May 1960. (27Q) Phillips, D. H.? Johnson, M. J.: Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (28Q) Phillips, K. L., Sallans, H. R., Spencer, J. F., Zbid. (29Q) Phillips, K. L., Spencer, J. F., others, J . Biochem. hficrobiol. Technol. Eng. 2, 81 (1960). (30Q) Potter, E. C., Everitt, G. E., J . Appl. Chem. (London) I O , 48 (1960). (31Q) Steel, R., Maxon, W. D.: Div. Agr. Food Chem., 138th Meeting, ACS, New York, September 1960. (32Q) Tsao, G. T., Kempe, L. L.,Ibid. (33Q) Tsao, G. T., Kempe, L. L., J . Biochem. Microbiol. Technol. En, J . Biochem. iWicro5iol. Technol. En!. 2, 49 (1960). (24T) Rotman, B., Bacteriol. Reo. 24, 251 (1960). (25T) Rozhkov, A. A , , others, Antibiotiki 5. 9 119601. (26?) Samsbnov, G. V., others, Med. Prom. S.S.S.R. 1960, No. 14, 3. (27T) Severa, Z . , Hoffman, J., Vondracek, M., Czech. Patent 94,333 (March 1960). (28T) Sobiczewski, W.:Szer, W., Lubinski, O., M e d . D6swiadczalna i Mik robiol. 12, 99 (1960). (29T) Tesar, A.. Czech. Patent 96,951 ’ (September 1960). 130T\ Thadani. S. B., Gen, C., Ghosh. D., Hindustan Antt’biotics’ Bull. ‘3, 69 (1960). (31T) Urks, M . , Cherkes, L.,Severa. Z., Med. Prom. S.S.S.II.1960, No. 11: 21. (32T) iVickerham. L. .J.. U . S. Patrnt, 2,960,445 (July 30, 1960). ~

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(lie).Zvara.

M., Lacok, P., Kolek. T R Z G I ~15, ~ Z23 R (1960).

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