Lactose freeze-dried

Table 7 Residual Organic Impurities in Lactose Freeze-Dried from 20% v/v Tert-Butanol/Water... 

Traditionally, glucagon preparations utilized therapeutically are chromatographically purified from bovine or porcine pancreatic tissue. (The structure of bovine, porcine and human glucagon is identical, thus eliminating the possibility of direct immunological complications). Such commercial preparations are generally formulated with lactose and sodium chloride and sold in freeze-dried form. Glucagon, 0.5-1.0 units (approximately 0.5-1.0 mg freeze-dried hormone), is administered to the patient by s.c. or i.m. injection. 

De Luca et al. [1.48] showed, that the addition of 5 % tertiary butyl alcohol (tBA) to aqueous sucrose and lactose solutions (up to 40 %) resulted in a frozen matrix, which could be easily freeze dried. De Luca demonstrated by DSC that the melting point rose distinctly (with 60 % solution to -10 °C), but the endothermic of melting returned to 25 %, indicating that not much water had frozen. In solutions with 5 % tBA the exothermic of crystallization became more visible and the melting of tBA could be recognized. 

De Luca, P. P., Klamat, M. S., Koida, C. Acceleration of freeze-drying Cycles of aqueous Solutions of Lactose and Sucrose with tertiary Buthylalcohol (tBA). Congr. Intern. Technol. Pharm. 5th Vol. 1, p. 439-447, 1989... 

Vries et al. [3.59] described the development of a stable parenteral dosage form of the cytotoxic drug E 09. E 09 dissolves poorly in water and its solution is unstable. With the addition of 200 mg of lactose per vial containing 8 mg of E 09, an optimum formulation was developed with respect to solubility, dosage of E 09 and length of the freeze drying cycle. DSC studies have been used to select the most effective parameters. The freeze dried product remains stable for 1 year when stored at 4 °C in a dark environment. 

Lactose may be obtained in two crystalline forms a-lactose and P-lactose (in addition to amorphous forms). The alpha form is obtained when water is incorporated into the lattice structure during crystallization (usually by supersaturation below 93.5°C) (5). Alternatively, the beta form does not contain water and exists as a non-hygroscopic and anhydrous form. Amorphous lactose is formed when either the crystallization is rapid or sufficient transient energy is introduced into the crystalline forms (74), i.e., spray drying (75), micronization and milling (76), freeze-drying, and anti-solvent crystallization (77). 

When a lactose solution is dried rapidly, its viscosity increases so quickly that crystallization cannot take place. The dry lactose is essentially in the same condition as it was in solution, except for removal of the water. This is spoken of as a concentrated syrup or an amorphous (noncrystalline) glass. Various workers have shown conclusively that lactose in milk powder (spray, roller, or freeze-dried) is noncrystalline and exists in the same equilibrium mixture of a- and /3-lactose as existed in the milk prior to drying (Zadow 1984). 

Powdered bioadhesive formulations have attracted much interest for their ability to overcome mucociliary clearance in the nasal cavity. For example, powder formulations of freeze-dried mixtures of insulin and excipients such as crystalline cellulose, hydroxypropyl cellulose, or carbopol 934 have been shown to enhance the absorption of insulin in dogs from the nasal cavity compared to freeze-dried mixtures of insulin and lactose as an excipient [28,31], The improved delivery was attributed to both the improved dispersion of insulin and the high... 

Fakes et al. [1.152] evaluated the moisture sorption behavior of mannitol, anhydrous lactose, sucrose, D-(+)-trehalose, dextran 40 and povidine (PVP K24) as bulking agents. Mannitol was found to be crystalline and non-hygroscopic before and after freeze-drying with RM 0.1-0.3% w/w at 25 °C and 10-60% RH. Anhydrous lactose, sucrose and trehalose were crystalline and relatively non-hygroscopic with RM 0.86, 0.15 and 9.2% respectively. After freeze-drying they where amorphous with RM 1.6, 2.5 and 1.2%, respectively, and adsorbed moisture in an increasing RH atmosphere. Lactose adsorbed 10% water and formed its crystalline hydrate at 55% RH. 

Craig et al. [1.176] assessed the behavior of amorphous lactose by MTDSC. The relaxation time of 10% freeze-dried amorphous lactose as a function of the difference between annealing (storage) temperature and is given in Figure 1.48.4 The relaxation time 15 K below is 10 h and 35 K below it is -250 h. The authors dis-... 

Fig. 1. 48.4. Relaxation time as a function of the difference between annealing temperature and Tg for a 10% amorphous freeze-dried lactose (Figure 5 from [1.1 76], with permission of Pharmaceutical Research)...

Kett et al. [1.162] studied Tg in freeze-dried formulations containing sucrose as a function of relative humidity and temperature during storage by TMDSC and ther-mogravimetric analysis. Craig et al. [1.163] found it helpful to asses the relaxation behavior of freeze-dried amorphous lactose by MTDSC. Relaxation times were calculated from measurements of Tg, and the magnitude of the relaxation endotherm. Scannnig was performed at 2°C/min with a modulation amplitude of 0.3 °C and a period of 60 s. 

Fig. 1.101.1. Equilibrium water content in two different freeze-dried products, each with two different amounts of product per vial. The equilibrium data are extrapolated from the +25 and +40 °C values. SV1, U and SV8 as in Figure 1.100 1,25 mg of lactose 2, 100 mg of lactose ...

Maa et al. [3.84] used spray drying and spray freeze-drying (see Chapter 5, [5.13, 5.14]) to produce protein powders for inhalation from deoxyribonuclease (rhDNase) and anti-IgE monoclonal antibody (anti-IgE Mab) with lactose as carrier. Spray freezedrying produced light and porous protein particles with superior aerosol performance. 

Freeze-dried liposomes loaded with doxorubicin (DXR) have been stored for 6 months at temperatures between -20 and +50 °C. Up to 30 °C, no sign of degradation was found, but at 40-50 °C, well below the Tg of the dried cake, the total DXR content and the retention of the drag after dehydration decreased, whereas the size of the liposomes increased to a certain extent. The stability with RM below 1% was better than with RM 2.5-3.5%. Lactose, trehalose and maltose have similar lyoprotectant properties, whereas liposomes with sucrose showed an increase in size. 

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