J.T. Carstensen

Amorphous-to-Crystalline Transformation of Sucrose

The transformation of amorphous sugar in the form of lyophilized spheres into crystalline sucrose was studied. The lyophilisate, when exposed to moist atmospheres, picks up moisture to a constant weight. The amount of moisture addition is a function of relative humidity of the atmosphere and temperature. The loose “lyophilisate structure” collapses to form a denser amorphous phase (“hydrated amorphate”). After a lag time which varies with relative humidity of the atmosphere and temperature, the hydrated amorphate loses moisture (weight) and, in the process, forms crystalline sucrose. The phase nature of the hydrated amorphate is equivalent to an aqueous solution that is supersaturated with respect to crystalline sucrose. A model was developed for the lag time which accounts for the experimental results.

Effect of Moisture on the Stability of Solid Dosage Forms

AbstractIt has long been known that moisture affects the stability of some drug substances. Aspirin is a classical example. Aspirin is not wet granulated. Even though the water is driven off in a wet granulation, there is still sufficient moisture stress in the process to induce excessive decomposition on subsequent storage. Dry methods (slugging, roller compaction) are therefore resorted to. In other instances, the moisture sensitivity of a drug may warrant using a hard shall capsule approach. This presumes that the drug substance is not particularly hygroscopic, since, otherwise, the capsule shell will provide an unwanted source of moisture.

Nucleation phenomena in amorphous sucrose systems.

Abstract This study investigated the phase transformation of amorphous to crystalline sucrose. Particular attention was paid to the nucleation phenomenon, and a method was developed to isolate nucleation kinetics from crystallization kinetics. Using this method and a simple mathematical model, various nucleation parameters could be determined. Additionally, the effects that additives, temperature, and relative humidity have on the inhibition or acceleration of nucleation were examined and are reported.

Physical and Chemical Properties of Calcium Phosphates for Solid State Pharmaceutical Formulations

AbstractThe physical and chemical properties of pharmaceutical phosphates are reviewed, with particular emphasis on chemistry of syntehsis, nomenclature, physico-chemical properties and tableting characteristics (other than Athy-Heckel qualities, which are covered elsewhere (Carstensen et al., 1989) and dissolution characteristics.

Physical model for release of drug from gelforming sustained release preparations

Certain sustained release preparations contain a substance which, when exposed to an aqueous medium, forms a gel. Liquid will continue to penetrate the gel layer with time (θ) and the release of drug is both a function of liquid penetration rates (α) and diffusion of drug through the gelled layer (with a permeation coefficient of II). The thickness of the layer will be a function of time, because as liquid penetrates, more gel is formed. Development of this model leads to a third-power equation for the amount of drug released (m) as a function of time: m = aθ3 + bθ2 + cθ; the coefficients a, b and c contain an integral: ƒ10 exp[(−π/α)(1/u)du which is evaluated graphically and found equal to 0.93 exp[−2.6π/α]. The data by Bamba et al. (1979) were used to demonstrate that the fit of experimental data to the third-power equation is a good as or superior to conventional plotting techniques.

Effect of Change in Shape Factor of a Single Crystal on Its Dissolution Behavior

AbstractPurpose. To study the effect of change in the shape factor of real crystals on their dissolution behavior using a potassium dichromate crystal as a model for particulates in general. Methods. A model geometry (parallelepiped) has been suggested for a dissolving particle. Single crystals of potassium dichromate which are monoclinic prisms were grown individually from supersaturated solutions at 40°C. Dissolution studies were carried out on five such crystals in 0. 0.1N H2SO4 at 25°C and a stirrer speed of 50 ± 1 rpm. The five crystals had different degrees of non-isometricity. Initial dimensions of the crystals were measured using image analysis techniques. The shape factor of the dissolving crystal as a function of time was obtained indirectly from the dissolution data. Results. The shape factor of a single crystal changed significantly after about 50% dissolution. The nature of this change depended on the degree of non-isometricity of the crystal. The change in shape factor of the dissolving crystal was accounted for in the Hixson-Crowell cube root law, and a modified form of the cube root equation was developed. This equation for dissolution explained the observed upward curvature in the cube root law plot. Conclusions. The shape factor for any non-isometric particle cannot be considered to be constant over the dissolution event, as is commonly assumed. This change has an appreciable effect on the dissolution behavior of crystals. This study is particularly of significance for elongated shapes like needles and platelets. By the methodology described here, it was possible to determine the initial shape factor of the crystal and the intrinsic dissolution rate constant.

Sampling in Blending Validation

AbstractIt is shown by a short statistical experiment, that sampling size in blending validation prior to the point where blending is as complete as it can be, is related to the size of the sample by being inverse function of the weight of the sample. The use of small thieves of the size of the dosage unit are apt to cause mechanical separation, and bias the results from the validation experiments. If the powder mixture is adequatly blended, then scaling can be carried out by considering the mass to be of a binomial distribution.The article is a preliminary article and will be followed by work done on larger matrices. It is noted that it is educational in nature, attempting to show in an easy manner what the parameters used and what the effects are. In the work of blending, experimental results usually have large variation, and for such considerations, simulation, as presented here, is a more fruitful approach.

The Athy—Heckel equation applied to granular agglomerates of basic tricalcium phosphate [3Ca3PO4)2·Ca(OH)2]

Abstract It is shown that direct compression grade tricalcium phosphate yields linear Heckel plots only if the particle density used is that obtained by liquid pycnometry or mercury porosimetry. If the true density is used (i.e. that obtained by gas displacement), then linearization is not obtained in a pressure range where bonding evidently occurs. It is shown that the pore volume in the range of diameters from 0.5 to 2 μm decreases as tableting pressure increases, and that bonding is associated with the loss of pores of this size.

Examination of a modified Arrhenius relationship for pharmaceutical stability prediction

Abstract A modified Arrhenius relationship was derived and used to treat simulated accelerated stability data. The results obtained were compared to those when the same data were treated according to the traditional method. The modified method presented here is easy to apply and in many cases yields a narrower predicted room temperature stability interval than does application of the traditional Arrhenius method.

Compression cycles in tableting

Abstract When powders are compressed to make a tablet, the powder is placed within a die and compressed by two punches. In general the act of compression is considered to occur in five stages: (a) first the powder rearranges to its closest packing, then (b) the particles deform elastically. (c) Beyond the elastic limits the particles will either fracture or deform plastically, and either of these processes leads to interparticulate bonding, i.e. gives rise to a tablet. (d) After release of the upper punch there is a relaxation of stresses in the bonded mass, and this is followed by (e) ejection of the tablet from the die. It is conventional to describe these processes by monitoring either the die wall pressure ( F ) or the lower punch pressure ( P l ) as a function of the upper punch pressure ( P ). These two types of cycles are conventionally described in the literature by assuming the solid to be a non-porous body. The cycles exhibit a hysteresis loop, and it is shown here that the consequence of considering the body nonporous throughout is that the hysteresis area of the cycles is either a quadratic or a linear function of the maximally applied pressure.